bims-tuinly 2026-07-19 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–07–19
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Correction: An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.
Tumor and Stromal Sphingolipid Imbalance Are Associated with T Cell Tissue Residency in Glioblastoma.
Tumor infiltrating lymphocytes in glioblastoma: immunobiology and translational implications.
The tumoural landscape of lymphocytes and immune pathways in immunotherapy-treated melanoma patients.
Diverse origin and nature of tumor-infiltrating lymphocytes: the infection hypothesis.
Tumor-Infiltrating Lymphocytes as Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: Added Value of Morphological Characterization Beyond Quantification.
Enhancing Translation of H&E to IHC with Robust Tumor-Infiltrating Lymphocytes Quantification Using Deep Generative Models: A Feasibility Study.
Challenges in immunotherapy and targeted therapy era of advanced cutaneous melanoma: Toxicities, resistance, outcomes.
Targeting DNMT1 augments anti-tumor CD8⁺ T cell function.
HPV viral load predicts immune exhaustion and prognosis in cervical neoplasia.
Selective Depletion of Tumor-Infiltrating CD4+CCR8+ Tregs by AZ084, a Novel CCR8 Antagonist.
Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.
Lactate Dehydrogenase-5 and Tumor-Infiltrating Lymphocytes in Prostate Cancer Patients Undergoing Radical Hypofractionated Radiotherapy.
CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells.
Endothelial protein C receptor expression as a marker of reduced metastatic risk in primary melanoma.
Beyond density: mapping the functional landscapes of macrophage-T lymphocyte niches in the tumor microenvironment.
From Excision to Immunity: The Full Spectrum of Modern Melanoma Treatments.
TP53 mutation-biased CD8+ T cell exhaustion drives lethal outcome and therapy resistance in urothelial carcinoma.
Safety and Feasibility of Infusing Ex Vivo Expanded Allogeneic Canine Natural Killer Cells for the Treatment of Metastatic Solid Tumours.
Cartilage Oligomeric Matrix Protein (COMP) Correlates with Disease Progression, Selected Immune Checkpoint Molecules and SIGLEC9 in Colorectal Cancer.
NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.
NK-like and networked CD8 + T cell immunity mediates exceptional HIV control.
Tumor infiltrating lymphocytes as a predictor of adjuvant avelumab efficacy in patients with high-risk triple negative breast cancer.
A 38-color spectral panel for cost efficient characterization of T cell therapy products.
Spatial Configuration of Pancreatic Cancer Is Associated with Disease Recurrence after Neoadjuvant Therapy and Curative-Intent Resection.
Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice.
LysoPS-GPR34 axis enhances tumor-associated macrophages efferocytosis to promote immune escape in gastric cancer peritoneal metastasis.

Front Bioinform. 2026 ;6 1920827

Correction: An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.

Frontiers Production Office

  [This corrects the article DOI: 10.3389/fbinf.2026.1764743.].

Keywords:  automated annotation; deep learning; lung adenocarcinoma; pathology; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fbinf.2026.1920827
Cancers (Basel). 2026 Jul 06. pii: 2168. [Epub ahead of print]18(13):

Tumor and Stromal Sphingolipid Imbalance Are Associated with T Cell Tissue Residency in Glioblastoma.

Chase M Walton, Elif Percin, Han Gyul Lee, Odai Darawsha, Ben A Strickland, Besim Ogretmen.

   BACKGROUND/OBJECTIVES: T cells within solid tumors often switch from a recirculating to a tissue-resident state, which may blunt antitumor activity, but the signal driving this switch in vivo remains unclear. We asked whether alterations in sphingosine-1-phosphate (S1P) signaling in tumor or the surrounding stromal cells are associated with T cell residency in glioblastoma (GBM).
METHODS: We analyzed five single-cell RNA-sequencing cohorts: three human glioma datasets, an in-house mouse CT2A glioblastoma cohort, and a human melanoma tumor-infiltrating lymphocyte cohort. T cell egress and tissue-residency programs, together with stromal S1P production and degradation, were scored per cell using curated gene modules. Cell-state contrasts were quantified as Cohen's d, and sample-level coupling as Spearman ρ.
RESULTS: In human GBM, T cell residency programs were elevated in CD4+ helper and regulatory T cells in tumors compared with low-grade glioma controls. In mouse CT2A-derived GBM tumors, stromal S1P production correlated negatively with T cell residency across four independent stromal cell types. In human GBM microglia, S1P production was reduced compared with control microglia. The same CD8+ residency phenotype was replicated in CD3-sorted GBM tumor-infiltrating lymphocytes (TILs) and in melanoma TILs.
CONCLUSIONS: A loss of stromal S1P production accompanies T cell tissue residency in GBM. Thus, stromal S1P metabolism is a candidate axis for modulating T cell recirculation and TIL biology in GBM. These findings are transcriptomic associations from single-cell RNA sequencing that do not directly measure S1P metabolite levels or signaling activity and will require functional and lipidomic validation.

Keywords:  ceramide; glioblastoma; melanoma; single-cell RNA sequencing; sphingosine-1-phosphate; tissue-resident memory; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers18132168
NPJ Precis Oncol. 2026 Jul 13. pii: 274. [Epub ahead of print]10(1):

Tumor infiltrating lymphocytes in glioblastoma: immunobiology and translational implications.

Cameron M Hill, Chibueze D Nwagwu, Angel O Odukoya, Brian Hsueh, Anthony Z Wang, Gavin P Dunn.

Glioblastoma (GBM) poses unique challenges to immunotherapy, owing to its low tumor mutational burden, profound antigenic heterogeneity, and highly immunosuppressive microenvironment. Observations of tumor-infiltrating lymphocytes (TILs) in human GBM differ from those in syngeneic orthotopic murine models: whereas TILs in several widely used murine glioma models display an abundance of exhausted T cells, patient tumors are enriched for clonally expanded granzyme K⁺ T cells of uncertain function. We review the current understanding of the brain tumor immunity cycle in GBM, highlight the translational implications of TIL biology, and evaluate emerging TCR-based approaches, including adoptive TILs transfer, neoantigen vaccines, and engineered receptors. A refined focus on identifying and harnessing tumor-selective T cells may enable more rational, personalized immunotherapies for GBM.

DOI: https://doi.org/10.1038/s41698-026-01330-3
Genes Immun. 2026 Jul 15.

The tumoural landscape of lymphocytes and immune pathways in immunotherapy-treated melanoma patients.

Vinícius Gonçalves de Souza, Bruna Pereira Sorroche, Renan de Jesus Teixeira, Hendrigo Nunes, Ana Carolina Laus, Vinícius de Lima Vazquez, Daniele Moraes Losada, Lidia Maria Rebolho Batista Arantes.

Tumor-infiltrating lymphocytes (TILs) shape melanoma behavior and response to immunotherapy, but the links between immune regulation, TIL patterning, and outcomes remain unclear. We retrospectively studied 32 primary melanoma samples from patients treated with anti-PD-1 therapy. Histopathologic TILs were classified as brisk or non-brisk, and primary tumors underwent targeted immune transcriptomic profiling (NanoString nCounter Human Immunology panel). External validation was performed with 96 TCGA-SKCM primary tumors. Brisk tumors displayed broad upregulation of immune transcripts, with enrichment of adhesion pathways (directed global significance scores - DGSS = 2.15) and MHC class II antigen presentation (DGSS = 2.128). Cross-cohort comparison identified 22 shared differentially expressed genes, with ZAP70 remaining significant in both datasets. Brisk tumors also showed higher total TIL (p = 0.036), cytotoxic-cell (p = 0.0095), and Th1 (p = 0.027) scores. Response-associated genes differed by TIL pattern, and subgroup-specific gene scores predicted anti-PD-1 benefit in brisk (4-gene, Area under curve - AUC = 1.000) and non-brisk (3-gene, AUC = 0.852) tumors; the non-brisk score remained independently associated with response (p = 0.029). Higher scores were also associated with prolonged survival. Integrating histopathological TIL patterning with immune transcriptomics may refine prognostication and support immunotherapy stratification in melanoma.

DOI: https://doi.org/10.1038/s41435-026-00406-1
J Immunother Cancer. 2026 Jul 16. pii: e015822. [Epub ahead of print]14(7):

Diverse origin and nature of tumor-infiltrating lymphocytes: the infection hypothesis.

Candelaria Gomez-Manzano, Dong Ho Shin, Christopher Alvarez-Breckenridge, Andrew G Gillard, Golnaz Morad, Vinay K Puduvalli, Marta M Alonso, Frederick F Lang, Juan Fueyo.

  In the 19th century, Rudolf Virchow observed lymphocyte infiltration in tumors and suggested a potential link between cancer and inflammation. Current explanations for the origin of tumor-infiltrating lymphocytes are based on the interaction between cancer cells and the immune system. This model was proposed before it was recognized that tumors are frequently infected or colonized by microbial elements, suggesting the presence of bacteria-specific and virus-specific T cells within tumors. While several aspects of this microbial experience remain under investigation, their impact on the tumor microenvironment and antitumor immune response may be significant, as the pathogens may elicit the direct or indirect recruitment of tumor-infiltrating lymphocytes. This "Infection Hypothesis" regarding the origin of tumor-infiltrating lymphocytes complements the classical tumor immunoediting hypothesis, offers new avenues for a comprehensive understanding of the tumor ecosystem, and highlights the need for more nuanced cancer treatment approaches that account for the potential interconnected roles of lymphocytes and pathogens in the tumor milieu.

Keywords:  Immunotherapy; Oncolytic virus; Solid tumor; Tumor infiltrating lymphocyte - TIL; Viral-specific T cells

DOI:  https://doi.org/10.1136/jitc-2026-015822
Cancers (Basel). 2026 Jun 25. pii: 2065. [Epub ahead of print]18(13):

Tumor-Infiltrating Lymphocytes as Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: Added Value of Morphological Characterization Beyond Quantification.

Juan Azcárate, Anna Petit, Teresa Soler-Monsó, Eugenia Quirós, Andrea Vethencourt, Agostina Stradella, Amparo García-Tejedor, Maria Jesús Pla-Farnos, Héctor Pérez-Montero, Anna Gumà, Raúl Ortega, Diana Pérez, Cristina Capó, Mar Varela, Luis M Molinos-Albert, María Del Rosario Taco-Sánchez, Esther Guerra, Jan Bosch-Schips, August Vidal, Evelyn Martínez-Pérez, Sonia Pernas, Miguel Gil-Gil, Catalina Falo.

  Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are recognized predictors of response to neoadjuvant chemotherapy (NACT) and prognosis in breast cancer, particularly in triple-negative (TN) and HER2-positive subtypes. However, the additional predictive value of morphological features of the inflammatory infiltrate beyond TIL quantification is not fully established. We aimed to assess the predictive value of TILs for response to NACT in breast cancer and to determine whether morphological characteristics of the inflammatory infiltrate enhance predictive accuracy. Methods: We analyzed 477 patients with stage II-III breast cancer treated with NACT between 2009 and 2016. Diagnostic core needle biopsies were prospectively re-evaluated. TILs were quantified according to International TILs Working Group recommendations. Morphological features of the infiltrate, including cell composition (lymphocytic vs. plasma cell-rich), heterogeneity, and localization, were evaluated using standardized criteria. Pathologic complete response (pCR) was defined as absence of invasive tumor in the breast and in the axillary lymph nodes (ypT0/Tis ypN0). Univariate and multivariate logistic regression analyses were performed to assess the predictive value of TILs (quantitative and morphological assessment) to achieve pCR for the entire cohort and by surrogate molecular subtype. Results: A TIL cutoff of >20% was identified as optimal for predicting pCR. High TILs were significantly associated with high-grade tumors, elevatedKi67, HER2-positive and TN subtypes, presence of plasma cells, and intraepithelial and heterogeneous infiltrates. In the overall cohort, TILs > 20% significantly increased the likelihood of pCR (OR 3.9, 95%IC 2.5-6.0, p < 0.001) and was an independent predictor of pCR. A combined variable incorporating TIL level and homogeneity improved predictive performance, with homogeneously high TILs emerging as a strong predictor of pCR (OR 5.521, 95%CI 3.174-9.603, p < 0.01). Plasma cell-rich and intraepithelial infiltrates were also associated with higher pCR rates (respectively, OR 2.7, 95%CI 1.5-5.0, p = 0.001 and OR 2.8, 95%CI 1.6-5.0, p < 0.001). Subtype-specific analyses confirmed the predictive value of TILs in TN tumors, but not in HER2-positive ones. Notably, in luminal B-like tumors, high TILs were the only independent predictor of response (OR 17.982, 95%CI 3.115-103.815, p = 0.001). Conclusions: TIL assessment on routine H&E-stained biopsies is a robust predictor of response to NACT in breast cancer that is readily available, cost-neutral and does not require additional techniques. Integration of simple morphological features significantly enhances predictive accuracy and may refine treatment stratification, particularly in luminal B-like tumors.

Keywords:  breast cancer; heterogeneity; intraepithelial infiltrate; luminal B breast cancer; neoadjuvant chemotherapy; plasma cells; predictive biomarkers; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3390/cancers18132065
J Imaging Inform Med. 2026 Jul 16.

Enhancing Translation of H&E to IHC with Robust Tumor-Infiltrating Lymphocytes Quantification Using Deep Generative Models: A Feasibility Study.

Doa Kim, Jiseon Kang, Hee Jin Lee, Ji-Seon Jeong, Miseon Lee, Byung-Kwan Jeong, Uiree Jo, Namkug Kim.

  Breast cancer is the leading cause of female oncological mortality, making treatment response prediction a priority. While tumor-infiltrating lymphocytes (TILs) are recognized as prognostic biomarkers, visual quantification on hematoxylin and eosin (H&E) slides suffers from interobserver variability. Virtual H&E-to-IHC stain translation represents a potential alternative to conventional, labor-intensive IHC. In this feasibility study, we developed a deep generative framework to synthesize virtual IHC patches from H&E patches and an automated pipeline for TILs quantification. To facilitate H&E-IHC image alignment, H&E slides were destained and restained for IHC, followed by a coarse-to-fine registration. Our framework incorporates two key components for better synthesis of TIL-specific chromogen: (1) a spatial attention mechanism guided by a cell segmentation map to focus on small TILs and (2) a chromogen loss function based on color separation for accurate diaminobenzidine (DAB) or alkaline phosphatase (AP) synthesis. Furthermore, we propose a TILs quantification pipeline designed to account for cells in overlapping regions. Integrating spatial attention and chromogen loss significantly improved performance, reducing mean absolute error (MAE) from 12.793 to 9.480 for DAB and from 21.113 to 17.755 for AP (p < 0.001 for both) per patch in the best-performing model. Reader studies demonstrated that the automated pipeline achieved moderate to high absolute count agreement with pathologists (intraclass correlation coefficient (ICC), 0.565-0.852) and strong relative density ranking (Spearman, 0.721-0.798) that exceeded inter-reader consistency. Furthermore, visual scoring confirmed that synthesized chromogens were comparable to ground truth IHC (p = 0.640).

Keywords:  Deep generative model; H&E-to-IHC stain translation; Image-to-image; Tumor-infiltrating lymphocytes (TILs) quantification

DOI:  https://doi.org/10.1007/s10278-026-02043-6
Pathol Res Pract. 2026 Jul 08. pii: S0344-0338(26)00266-9. [Epub ahead of print]286 156613

Challenges in immunotherapy and targeted therapy era of advanced cutaneous melanoma: Toxicities, resistance, outcomes.

Zhenyu Fan, Yeliang Mei, Kaituo Liu, Yingjie Zhang, Linlin Shi.

  In current intensive care units (ICUs), advanced cutaneous melanoma is no longer merely a terminal complication, but has evolved into a dynamic treatment-related syndrome. Immune checkpoint inhibitors can achieve durable disease control, but they may trigger fulminant multi-organ toxicity, requiring rapid identification and intervention to preserve anti-tumor benefits. BRAF/MEK targeted therapy enables rapid tumor debulking, but it easily induces severe events such as hyperprogression and tumor lysis syndrome due to drug resistance. Cellular therapies like tumor-infiltrating lymphocytes (TILs) offer new options for patients with previous treatment failure, but also bring ICU-related risks including cytokine release syndrome. This review proposes that ICUs should serve as upstream collaborators in melanoma care. It outlines key diagnostic and therapeutic pathways for various emergencies based on four core principles: toxicity recognition, standardized intervention, dynamic risk monitoring, and safe restart of systemic therapy. It also notes that future individualized management can be realized by integrating multi-dimensional indicators, to coordinate short-term organ support and long-term disease control, and improve the survival prognosis and quality of life of critically ill patients with melanoma.

Keywords:  Advanced Cutaneous Melanoma; BRAF/MEK Targeted Therapy; ICU Critical Care; Immune Checkpoint Inhibitors (ICI); Tumor‑infiltrating Lymphocytes (TILs)

DOI:  https://doi.org/10.1016/j.prp.2026.156613
bioRxiv. 2026 Jul 06. pii: 2026.07.03.736412. [Epub ahead of print]

Targeting DNMT1 augments anti-tumor CD8⁺ T cell function.

Maya G Deshmukh, Danielle Sohai, Kamal Obbad, Koonam Park, Simon Milette, Peili Gu, Henna S Nam, Andrew J Daniels, Krasimir A Spasov, Michael Hurwitz, Samuel Katz, Richard A Flavell, Karen S Anderson, Marcus Bosenberg, Goran Micevic.

Chronic stimulation of CD8⁺ T cells within the tumor microenvironment (TME) induces a hypofunctional state characterized by diminished cytotoxicity and functionally impaired anti-tumor function, known as exhaustion. Exhaustion is associated with epigenetic changes that remain relatively stable despite interventions like immune checkpoint inhibition (ICI). Although epigenetic changes are potentially reversible, reports of therapeutic strategies to effectively restore function in exhausted CD8⁺ T cells remain limited. Here, we report DNA methyltransferase 1 (DNMT1) inhibition (DNMT1i) in counteracting CD8 + T cell dysfunction during the anti-tumor response. We show that DNMT1i synergizes with ICI to rescue the tumor cell killing activity of chronically stimulated CD8⁺ T cells in a melanoma model. DNMT1i mitigates transcriptional features of exhaustion while inducing a divergent effector program. DNMT1i attenuates the global increase in chromatin accessibility associated with exhaustion and enables epigenetic remodeling of the exhausted chromatin landscape upon restimulation. Finally, DNMT1i enhances the effector function of melanoma patient-derived tumor infiltrating lymphocytes after prolonged ex vivo expansion. These studies establish DNMT1 targeting as a promising strategy to counteract CD8⁺ T cell exhaustion and potentiate ICI efficacy.

DOI: https://doi.org/10.64898/2026.07.03.736412
Front Immunol. 2026 ;17 1840435

HPV viral load predicts immune exhaustion and prognosis in cervical neoplasia.

Yibo Guo, Yuanrui Liu, Yongjian He, Yuzhao Zhang, Ling Li, Weiguo Lu, Zhanfeng Zhang.

   Objective: Persistent infection with high-risk human papillomavirus (HPV) is the primary cause of cervical cancer; however, the prognostic role of HPV viral load and its association with the tumor immune microenvironment remain incompletely understood. This study aimed to systematically evaluate the association between HPV viral load and disease progression, prognosis, and tumor immune microenvironment in patients with cervical cancer.
Methods: A retrospective cohort of 278 patients with cervical neoplasia was analyzed. HPV viral load was quantified and log10-transformed. Patients were categorized into low- and high-viral load groups using segmented regression. Clinical characteristics, recurrence, metastasis, and survival were compared. Immune parameters (CD3+, CD4+, CD8+, FOXP3+ T cells, programmed death-ligand 1 [PD-L1] expression), serum tumor markers (squamous cell carcinoma antigen [SCC], cancer antigen 125 [CA125], CA199, carcinoembryonic antigen [CEA]), Ki67, p16, and sex hormone levels were assessed.
Results: High HPV viral load (log10 ≥5.6) was significantly associated with advanced disease stage (p < 0.001), lymph node metastasis (28.3% vs. 13.5%, p = 0.002), and higher recurrence rates (27.4% vs. 13.0%, p = 0.002). Five-year overall survival (OS) (68.5% vs. 87.3%) and recurrence-free survival (RFS) (59.3% vs. 82.1%) showed a trend toward worse outcomes in the high viral load group, but the differences were not statistically significant (log-rank p = 0.38 and p = 0.068, respectively). Multivariable Cox analysis confirmed high viral load as an independent predictor of recurrence (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.32-3.61, p = 0.002). High viral load correlated with reduced tumor-infiltrating lymphocytes (TILs) (CD3+: 12.1% vs. 18.3%, p = 0.001), lower PD-L1 positivity (36.4% vs. 63.2%, p = 0.045), and higher Ki67 expression (58.3% vs. 42.5%, p = 0.003). Combining viral load with serum SCC improved prediction of high-grade lesions (area under the curve [AUC] 0.78 vs. 0.73, p = 0.02) and recurrence (C-index 0.71 vs. 0.65). Machine learning models ranked viral load as the top predictor. Post-treatment viral load decline was significantly associated with lower recurrence risk (odds ratio [OR] 4.12 for slow decline, p = 0.02). In premenopausal women, estradiol levels correlated positively with viral load (ρ = 0.31, p = 0.003) and disease severity. A correlation network revealed a cluster linking high viral load, low immune infiltration, and high proliferation. The prognostic effect of viral load was consistent across HPV types and was more pronounced in advanced-stage patients (interaction p = 0.09).
Conclusion: High HPV viral load is an independent predictor of poor prognosis in cervical cancer, associated with an immunosuppressive tumor microenvironment and enhanced proliferative activity. Incorporating viral load into routine assessment may improve risk stratification and guide personalized treatment strategies, particularly for patients with high viral load who may benefit from immune-enhancing therapies.

Keywords:  biomarker; cervical cancer; cervical intraepithelial neoplasia; human papillomavirus; immunosuppression; tumor-infiltrating lymphocytes; viral load

DOI:  https://doi.org/10.3389/fimmu.2026.1840435
Cancer Sci. 2026 Jul 12.

Selective Depletion of Tumor-Infiltrating CD4+CCR8+ Tregs by AZ084, a Novel CCR8 Antagonist.

Yepeng Mao, Ziqi Tao, Shuna Liu, Zhijie Liu, Yuelu Zhang, Lingfei Zhou, Lina Yan, Ting Wang, Wenwen Shang, Jianfang Lou, Xi Huang, Xin Fu, Fang Wang.

  Regulatory T cells (Tregs) are key mediators of immunosuppression in ovarian cancer, yet strategies for selectively targeting tumor-infiltrating Tregs remain limited. CD4+CCR8+ Tregs have been proposed as a highly suppressive subset, but their functional relevance and therapeutic potential require further investigation. Here, we demonstrate that CCR8 is preferentially expressed on tumor-infiltrating CD4+ Tregs in syngeneic ID8 and B16 tumor models, accounting for a significantly higher proportion compared with CD4+ conventional T cells and CD8+ T cells (p < 0.001). Functionally, CD4+CCR8+ Tregs exhibited enhanced suppressive activity, markedly inhibiting IFN-γ production by CD8+ T cells (p < 0.01). The antagonist AZ084 significantly impaired Treg differentiation and alleviated Treg-mediated suppression in vitro (p < 0.01). In vivo, AZ084 treatment effectively suppressed tumor growth in both ovarian cancer and melanoma models (p < 0.01), accompanied by a reduction in tumor-infiltrating CD4+CCR8+ Tregs and an increase in CD8+ T cell infiltration and effector function (p < 0.05). Importantly, AZ084 had minimal impact on splenic immune cell composition (p > 0.05), suggesting limited systemic immunotoxicity. Collectively, our findings identify CCR8 as a selective marker and functional regulator of tumor-infiltrating Tregs. Targeting CCR8 with AZ084 represents a promising strategy to enhance antitumor immunity while preserving peripheral immune homeostasis, providing a potential therapeutic approach for ovarian cancer.

Keywords:  AZ084; CCR8; chemokine; ovarian cancer; regulatory T cells

DOI:  https://doi.org/10.1111/cas.70465
Front Immunol. 2026 ;17 1744549

Ablating Satb1 reprograms the differentiation trajectory of exhausted CD8+ T subsets to enhance antitumor immunity.

Linwei Wu, Haolin Jiang, Jianling Gao, Xiaolan Ji, Yu Chen, Zhenghao Ma, Xinying Li, Jin Wang, Yachen Zang, Ji Zhang, Xin Zhao, Xuefeng Wang.

   Introduction: Under chronic infections or in tumors, persistent antigen exposure drives CD8+ T cell exhaustion, a heterogeneous state encompassing a differentiation continuum from stem-like progenitor (Tpex) cells through transitory effector-like (Tex-int) cells to terminally exhausted (Tex-term) subsets. Among these T cell subsets, Tex-int cells serve as the primary population responsible for direct tumor cell killing. However, the intrinsic regulatory mechanisms that govern the Tpex-to-Tex-int transition remain incompletely defined.
Methods: In this study, we explore the role of special AT-rich sequence-binding protein 1 (SATB1) in the differentiation of Tex-int cells from their precursors. We observed downregulation of SATB1 during Tpex-to-Tex-int differentiation in tumors. Notably, the genetic ablation of Satb1 in T cells markedly expanded the population of tumor-infiltrating CD8+ T cells (CD8+ TILs).
Results: Ablating Satb1 not only promoted the differentiation of Tex-int cells from Tpex cells within the tumor microenvironment but also remodeled T cell differentiation in tumor-draining lymph nodes (TdLNs) by expanding the Tpex pool from tumor-specific memory CD8+ T cells (TTSM) and driving the Tpex1 to Tpex2 transition, thereby augmenting Tex-int production in tumors. Although early-stage Tex-int cells in Satb1-deficient mice displayed transient functional impairment relative to controls, this difference was no longer evident in late-stage tumors, where sustained Tex-int accumulation correlated with significantly suppressed tumor growth and prolonged survival.
Discussion: Our results identify SATB1 as a pivotal regulator of exhausted CD8+ T cell subset differentiation and suggest its targeting as a promising strategy to expand the Tex-int population for enhanced cancer immunotherapy.

Keywords:  Satb1; Tex-int cells; Tpex cells; effector-like Tex- int cells; stem-like Tpex cells; tumor immunity; tumor-infiltrating CD8+ T cells

DOI:  https://doi.org/10.3389/fimmu.2026.1744549
Cancers (Basel). 2026 Jul 03. pii: 2149. [Epub ahead of print]18(13):

Lactate Dehydrogenase-5 and Tumor-Infiltrating Lymphocytes in Prostate Cancer Patients Undergoing Radical Hypofractionated Radiotherapy.

Ioannis M Koukourakis, Kalliopi Platoni, Vassilis Kouloulias, Christina Yfanti, Stella Arelaki, Christos Kalaitzis, Anna Zygogianni, Michael I Koukourakis, Alexandra Giatromanolaki.

  Background/Objectives: Aerobic glycolysis is a standard mechanism that cancer cells use to support their anabolic processes. Lactate and proton production, byproducts of this LDHA-catalyzed transformation of pyruvate, may contribute to acidifying the tumor microenvironment and to repressing the cytotoxic activity of anti-tumor immune cells. Prostate cancer radiotherapy outcome could be diminished by cancer cell metabolism and immunosuppression. Methods: The tumor infiltrating lymphocyte (TIL) density was assessed in 110 prostate adenocarcinoma biopsies from patients treated with radical radiotherapy. Immunohistochemistry was performed to evaluate LDH5 expression by cancer cells (encoded by the LDHA gene). Results: Higher tumor stages (T3 and T4) were associated with lower TIL density (p = 0.02). Approximately half of the patients (51%) displayed strong LDH5 cancer cell expression, which was linked with advanced T-stage and higher Gleason scores (p = 0.05 and p = 0.01, respectively). High LDH5 expression was significantly correlated with low TIL density (p ≤ 0.0004). In univariate analysis, high LDH5 and low TIL density were associated with poor biochemical relapse-free survival (BRFS) (p ≤ 0.006). In multivariate analysis, TIL density, but not LDH5, was an independent predictor of BRFS (p = 0.03). Conclusions: LDH5 overexpression is associated with low tumor lymphocytic infiltration. Stratifying prostate carcinomas according to LDH5/TIL density identifies a group of patients with low TIL density and high LDH5 expression, who have a higher risk of tumor relapse. Targeting glycolysis to disrupt cancer cell metabolism offers an interesting research area for prostate cancer therapy.

Keywords:  LDH; anaerobic metabolism; prostate cancer; radiotherapy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers18132149
Cancer Immunol Res. 2026 Jul 16.

CD4+ T cells play distinct roles during the priming versus effector phases of immune checkpoint therapy-dependent tumor elimination by CD8+ T cells.

Samuel Ameh, Derek J Theisen, Mahima Thapa, Jackson S Turner, Abhinav Rangarajan, Christopher A Nelson, Aaron J Schmitz, Yuang Song, Ruan F Vieira Medrano, Cora D Arthur, J Michael White, Kathleen C F Sheehan, Daved H Fremont, Ali H Ellebedy, Hussein Sultan, Robert D Schreiber.

It is well established that CD4⁺ T cells play a critical role in facilitating immune checkpoint therapy (ICT). Although CD4+ T-cell function in lymph nodes during CD8⁺ T-cell priming has been well investigated, their requirement at the effector phase in the tumor is only now beginning to be appreciated. Herein, we used our major histocompatibility complex class II-negative (MHC-II-) sarcoma models to confirm that CD4⁺ T cells are essential not only during T-cell priming, but also to maintain T-cell effector function within the tumor. Depleting CD4⁺ T cells at the effector phase, after CD8+ T-cell priming had occurred, abolished ICT-induced tumor rejection despite the detection of tumor-specific CD8⁺ T cells and their intratumoral accumulation. CD4⁺ T cells were required for functional reinvigoration of CD8⁺ tumor-infiltrating lymphocytes (TIL) by ICT, leading to enhanced cytokine production, expression of cytotoxicity, and reduced exhaustion-without affecting CD8+ T-cell proliferation. Mechanistically, CD4⁺ T-cell function at the effector phase did not require CD40/CD40L signaling, which is necessary for efficient priming, but rather depended on IL-2 and IFNγ. Using a TCR-mimic monoclonal antibody (1G10) specific for the dominant neoantigen:I-Aᵇ complex on antigen-presenting cells formed during T3 sarcoma challenge, we further showed that ongoing MHC-II neoantigen presentation was necessary to sustain CD4⁺ T-cell help after priming. These findings reveal temporally distinct requirements for CD4⁺ T-cell help and establish a need for continuous CD4⁺/CD8⁺ T-cell cooperation as a prerequisite for anti-PD-1/anti-CTLA-4 ICT efficacy against MHC-II- tumors.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-1652
Melanoma Res. 2026 Jul 14.

Endothelial protein C receptor expression as a marker of reduced metastatic risk in primary melanoma.

Takayuki Fusumae, Takeru Funakoshi, Ikuko Hirai, Yoshio Nakamura, Keitaro Fukuda, Takashi Iwata, Masayuki Amagai, Keiji Tanese.

  Malignant melanoma has a strong propensity for early metastatic dissemination, yet conventional clinicopathological predictors such as Breslow thickness do not fully capture individual metastatic risk. The endothelial protein C receptor (EPCR) exerts context-dependent functions across malignancies, but its clinical significance in melanoma remains unclear. We retrospectively analyzed primary tumor specimens from 62 patients with invasive melanoma; 61 with complete outcome data formed the analytic cohort for metastasis analyses. EPCR expression in melanoma cells was evaluated by immunohistochemistry using semi-quantitative intensity and extent scores (0-3). Tumor-infiltrating lymphocytes were graded according to the Melanoma Institute Australia scoring system. Higher EPCR expression was associated with lower odds of documented lymph-node and distant metastatic involvement. In prespecified parsimonious multivariable logistic regression models adjusted for tumor thickness and ulceration, higher EPCR extent remained independently associated with reduced lymph-node involvement (adjusted odds ratio: 0.36, 95% confidence interval:, 0.17-0.70). EPCR expression showed a positive association with CD8+ tumor-infiltrating lymphocyte scores. Higher EPCR expression in primary melanoma was independently associated with reduced lymph-node involvement and with a CD8+-inflamed tumor microenvironment, suggesting EPCR may complement conventional pathological predictors of metastatic risk.

Keywords:  endothelial protein C receptor; immunohistochemistry; melanoma; neoplasm metastasis; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1097/CMR.0000000000001123
Front Immunol. 2026 ;17 1851873

Beyond density: mapping the functional landscapes of macrophage-T lymphocyte niches in the tumor microenvironment.

Serena Zilio, Adrien Rouault Montecino, Malvina Seradj, Ilaria Marigo, Armelle Prévost-Blondel, Elisa Peranzoni, Nadège Bercovici.

  The spatial arrangement of tumor-associated macrophages (TAMs) and T cells within distinct microanatomical niches is emerging as a key regulator of clinical outcome in solid tumors. Here, we propose a comprehensive review that integrates spatial insights with functional studies of macrophage and T cell heterogeneity, to elucidate how the physical crosstalk and the localization of these cells in the tumor microenvironment (TME) can impact the prognosis and the response to immunotherapy and, vice versa, how diverse immunotherapies can dynamically reshape the TME immune geography. We first review the heterogeneity of macrophages and tumor-infiltrating T lymphocytes (TILs) in TME, and the different types of TAM-TIL niches recently described by multidimensional proteomics and spatial transcriptomics, addressing their impact on tumor progression and response to immunotherapy. Building on our own work, we then dissect the anti-tumoral and pro-tumoral mechanisms operating in the different types of immune hubs. Next, we examine how tumor cues and therapeutic strategies can reprogram macrophages and T cells across functional and spatial dimensions, thereby promoting TME permissive to intraepithelial T cell infiltration and clinical response. Finally, we discuss how the integration of multi-omics and artificial intelligence are transitioning immuno-oncology from a cell-centric to a niche-centric paradigm, providing a roadmap for the design of next-generation therapies that precisely reprogram cellular dialogues within the tumor microenvironment.

Keywords:  TAM-TIL niches; cellular neighborhood; immune cell crosstalk; spatial biology; tumor microenvironment (TME); tumor-associated macrophages (TAMs); tumor-infiltrating T lymphocytes (TILs)

DOI:  https://doi.org/10.3389/fimmu.2026.1851873
Cancers (Basel). 2026 Jun 24. pii: 2043. [Epub ahead of print]18(13):

From Excision to Immunity: The Full Spectrum of Modern Melanoma Treatments.

Vimal Murugesan, Thusanth Thuraisingam, Danuta Radzioch.

  Cutaneous Melanoma is a biologically heterogeneous malignancy. Although recent therapeutic advances have improved survival, durable remissions remain elusive for many patients. Surgical excision with stage-appropriate margins and selective nodal staging remains the cornerstone of curative-intent management. In contrast, conventional cytotoxic chemotherapy now plays a limited, largely palliative role given its modest efficacy and substantial toxicity. Targeted therapy with BRAF/MEK inhibitors has improved outcomes in patients with BRAF V600-mutant melanoma, resulting in rapid tumor regression and meaningful survival benefits. However, long-term disease control is frequently compromised by adaptive resistance, commonly driven by MAPK pathway reactivation or compensatory PI3K/AKT signaling. In parallel, immune checkpoint inhibitors targeting PD-1, CTLA-4, and emerging pathways have reshaped treatment across disease stages, enabling deep and sometimes durable responses. Despite this progress, primary and acquired resistance, as well as acute and chronic immune-related toxicities, continue to pose significant clinical challenges. Current therapeutic strategies focus on rational combinations of targeted therapy, checkpoint blockade, IL-2-based approaches, oncolytic viruses, and adoptive cell therapies such as tumor-infiltrating lymphocytes to enhance response depth and durability. However, these intensified regimens carry increased toxicity risks, highlighting the need for improved patient selection and monitoring. Overall, emerging evidence supports a paradigm shift toward optimized treatment sequencing, response-adapted surgical strategies, and biomarker-guided personalization to maximize clinical benefit while minimizing toxicity.

Keywords:  chemotherapy; cutaneous melanoma; immunotherapy; surgery; targeted therapy

DOI:  https://doi.org/10.3390/cancers18132043
Br J Cancer. 2026 Jul 11.

TP53 mutation-biased CD8+ T cell exhaustion drives lethal outcome and therapy resistance in urothelial carcinoma.

Xiaohe Su, Kaifeng Jin, Han Zeng, Zhaopei Liu, Lingkai Zhang, Yawei Ding, Jiaxing Sun, Yuzhen Wu, Hailong Liu, Yuan Chang, Le Xu, Weijuan Zhang, Zewei Wang, Yu Zhu, Jiejie Xu.

BACKGROUND: Emerging evidence has underscored non-cell-autonomous roles of mutant p53 in reshaping the composition and functional state of tumour immune microenvironment (TIME). However, the impact of p53 status on the clinical relevance and functional differentiation of CD8+ T cells remains poorly understood in urothelial carcinoma (UC).
METHODS: Our study included 297 UC patients from two in-house cohorts and 871 UC patients from four public datasets to evaluate the impact of p53 status on the clinical implications of CD8+ T cells. Single-cell RNA sequencing, flow cytometry, immunohistochemistry, and bioinformatics analyses were performed to elucidate the role of p53 status in regulating CD8+ T cell polarisation and reshaping the TIME.
RESULTS: High CD8+ T cell infiltration correlated with favourable prognosis and improved survival following chemotherapy and PD-(L)1 blockade exclusively in p53-WT UC, while its association with prognosis and therapeutic benefit was abrogated in p53-mutant UC. Moreover, p53-mutant UC exhibited predominant infiltration of TIM3+ exhausted CD8+ T cells, accompanied by increased Treg and M2 macrophage infiltration.
CONCLUSIONS: The clinical significance and functional polarisation of CD8+ T cells in UC varied in a context-dependent manner according to p53 status. These findings provide novel insights to refine patient stratification and optimise personalised therapeutic strategies.

DOI: https://doi.org/10.1038/s41416-026-03548-1
Vet Comp Oncol. 2026 Jul 16.

Safety and Feasibility of Infusing Ex Vivo Expanded Allogeneic Canine Natural Killer Cells for the Treatment of Metastatic Solid Tumours.

Allison M Weisnicht, Fernanda Szewc, Monica Moonkyung Cho, Han-Yun Hannah Cheng, Swetha Ganesh, Lauren Mahoney, Kathryn Fox, Portia R Smith, Mallery Olsen, Rebecca M Richards, David M Vail, Christian M Capitini.

  Companion canines need advances in therapeutic options for solid tumour malignancies. Natural killer (NK) cell infusions offer a promising treatment modality in canines with solid tumours. Autologous natural killer products are limited by dysfunctional immunity and a manufacturing process that delays care whereas allogeneic NK cells offer the possibility of 'off-the-shelf' therapy to be administered from healthy donors. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy canine donors via density gradient separation. NK cells were expanded with recombinant human IL-2 and canine IL-21 with the addition of K562 feeder cells transfected with CD137 ligand and membrane bound human IL-15. Additional experiments included IL-12 during expansion. In vitro potency was assessed via co-culture with the D17-mKate2 canine osteosarcoma cell line. Three canines were enrolled in a phase 1 trial infusing ex vivo expanded allogeneic NK cells after lymphodepletion. Flow cytometric analysis confirmed successful expansion of canine NK cells with up to 50% of cells demonstrating NKp46+ after 14 days. Residual T cell numbers varied based on donor. The addition of IL-12 led to increased NK cell expansion. Incucyte demonstrated potency with increasing osteosarcoma cell death at higher effector to target ratios. Three canines with metastatic/refractory solid tumours were successfully lymphodepleted and infused with allogeneic NK cell products. The canines tolerated the infusions well. Canine allogeneic NK cells were successfully expanded and activated ex vivo, demonstrated potency in vitro and safety in vivo. Further studies will optimise the NK cell product and escalate dosing to reach the maximal tolerable dose.

Keywords:  IL‐12; NK cells; allogeneic; canine; clinical trial; osteosarcoma

DOI:  https://doi.org/10.1111/vco.70091
Int J Mol Sci. 2026 Jul 05. pii: 6032. [Epub ahead of print]27(13):

Cartilage Oligomeric Matrix Protein (COMP) Correlates with Disease Progression, Selected Immune Checkpoint Molecules and SIGLEC9 in Colorectal Cancer.

Piotr Limanówka, Anna Kot, Wiktor Wagner, Błażej Ochman, Sylwia Mielcarska, Agnieszka Kula, Miriam Dawidowicz, Dorota Hudy, Monika Szrot, Jerzy Piecuch, Zenon Czuba, Elżbieta Świętochowska, Iwona Gisterek-Grocholska, Dariusz Waniczek.

  Cartilage oligomeric matrix protein (COMP) influences extracellular matrix remodeling. We investigated its clinical, prognostic, and immunomodulatory significance in colorectal cancer (CRC). COMP was quantified via ELISA in 107 paired CRC and normal tissues. Expression was correlated with clinicopathological features, mutational profiles, microsatellite instability (MSI), tumor-infiltrating lymphocytes (TILs), immune checkpoints, and multiplex cytokine networks. For transcriptomic validation, the FieldEffectCrc dataset was used for Gene Set Enrichment Analysis (GSEA), and The Cancer Genome Atlas (TCGA) CRC cohort for survival analysis. COMP was significantly upregulated in CRC tissues (p < 0.001) and correlated with advanced T, N, and overall pathological stages (all p < 0.05, tau = 0.18, 0.21, and 0.23, respectively). High COMP expression was linked to restricted immune infiltration (reduced stromal TILs, p < 0.05, tau = -0.23), elevated levels in microsatellite stable (MSS) compared to MSI tumors (p < 0.01), and correlated positively with immune exhaustion markers (T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), galectin-9 (GAL9), sialic acid-binding Ig-like lectin 9 (SIGLEC9)). Transcriptomic data linked high COMP to worse disease-specific and progression-free survival, and enrichment in pro-tumorigenic pathways (epithelial-to-mesenchymal transition, angiogenesis, IL-6 signaling). COMP upregulation defines an immunosuppressive microenvironment in CRC, particularly in MSS tumors. It represents an important prognostic biomarker and potential therapeutic target for overcoming immunotherapy resistance.

Keywords:  SIGLEC9; TIM-3; cartilage oligomeric matrix protein; colorectal cancer; galectin 9; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/ijms27136032
Front Immunol. 2026 ;17 1755657

NOSIP overexpression promotes long-term persistence of CD8+ T cells during chronic infection.

Shihui Li, Toshikatsu Tamai, Yui Shinzawa, Sotaro Fujisawa, Yamato Tanabe, Makoto Utsunomiya, Hidetoshi Nakagawa, Junko Kurachi, Miki Koura, Eishiro Mizukoshi, Makoto Kurachi.

  Chronic antigen exposure drives CD8+ T cell exhaustion; however, strategies to maintain a long-lived, functional CD8+ T cell population under chronic stimulation remain unclear. In this study, we demonstrate that overexpression of nitric oxide synthase-interacting protein (NOSIP) enhances the persistence of antigen-specific CD8+ T cells under chronic antigen stimulation. Notably, NOSIP overexpression preserved a less differentiated CX3CR1neg subset and inhibited its progression toward an apoptosis-prone CX3CR1hi state, which was associated with reducing cell death and promoting long-term persistence. In a tumor model, NOSIP-overexpressing CD8+ T cells exhibited improved tumor control, indicating that NOSIP-mediated persistence confers superior antitumor capacity. Furthermore, NOSIP overexpression increased the responsiveness of CD8+ T cells to programmed death-ligand 1 blockade, suggesting that NOSIP may represent a promising therapeutic target.

Keywords:  CD8+ T cells; CX3CR1 subset differentiation; NOSIP; PD-L1 blockade responsiveness; chronic antigen stimulation

DOI:  https://doi.org/10.3389/fimmu.2026.1755657
bioRxiv. 2026 Jul 07. pii: 2026.07.02.735504. [Epub ahead of print]

NK-like and networked CD8 + T cell immunity mediates exceptional HIV control.

Aljawharah Alrubayyi, Anna K Traunbauer, Charles R Crain, Shaown Bhattacharyya, David R Collins, Hsinyen Huang, Clarety Kaseke, Umar Arshad, Xiaodong Lian, Aarthi Vijayakumar, Matthew A Getz, Mathias Lichterfeld, Xu G Yu, Bruce D Walker, Georg M Lauer, Gaurav D Gaiha.

Durable treatment-free remission remains a defining goal for people living with HIV (PLWH). Studies of spontaneous elite controllers have revealed that functional CD8⁺ T cells targeting structurally networked viral epitopes can mediate durable viral suppression 1,2 . However, rare reservoir-defined exceptional controllers within the spectrum of elite control 3-5 , characterized by the absence of intact provirus or proviruses confined to transcriptionally repressed genomic regions 6 , provide a unique opportunity to define mechanisms of cure-like immunity. Here, we integrate functional epitope mapping, single-cell transcriptomics, and infected cell elimination assays to identify networked HIV epitope targeting and a natural killer (NK)-like killer-cell immunoglobulin-like receptor (KIR)⁺ CD8⁺ T cell subset as key features of exceptional control. This NK-like subset was selectively enriched within HIV-specific, but not CMV-specific, CD8⁺ T cells from controllers, and was transcriptionally similar to highly cytotoxic subsets within the broader KIR + CD8 + T cell compartment. Flow cytometry revealed increased frequencies of KIR⁺ CD8⁺ T cells in exceptional controllers relative to antiretroviral therapy (ART)-suppressed individuals, and unexpectedly, enrichment of dual KIR + NKG2A + CD8⁺ T cells. Functional depletion of KIR⁺ CD8⁺ T cells significantly impaired the elimination of autologous HIV-infected CD4⁺ T cells, despite preserved recognition by proliferative networked HIV-specific CD8⁺ T cells. These findings thereby identify an NK-like KIR⁺ CD8⁺ T cell state as a previously unrecognized component of exceptional HIV immunity that complements networked epitope targeting, providing a novel framework for immunotherapeutic HIV cure strategies.

DOI: https://doi.org/10.64898/2026.07.02.735504
Clin Cancer Res. 2026 Jul 17.

Tumor infiltrating lymphocytes as a predictor of adjuvant avelumab efficacy in patients with high-risk triple negative breast cancer.

Maria Vittoria Dieci, Elisa Gasparini, Lorenzo Nicolè, Peter Schmid, Alberto Zambelli, Adolfo Favaretto, Federico Piacentini, Giulia Valeria Bianchi, Marta Mion, Antonella Ferro, Grazia Arpino, Alessandra Emiliani, Saverio Cinieri, Claudio Zamagni, Alessandra Gennari, Simon Spazzapan, Donata Sartori, Fable Zustovich, Stefano Tamberi, Lucia Del Mastro, Michelino De Laurentiis, Antonino Musolino, Katia Cagossi, Daniele Generali, Tommaso Giarratano, Filippo Giovanardi, Gian Luca De Salvo, Pierfranco Conte, Valentina Guarneri.

PURPOSE: We aimed to investigate the prognostic and predictive value of tumor infiltrating lymphocytes (TILs) for adjuvant immunotherapy in high-risk early TNBC.
PATIENTS AND METHODS: The phase III A-BRAVE trial randomized 466 patients with high-risk early TNBC to adjuvant avelumab or observation after standard therapy. Inclusion criteria allowed two strata: Stratum A (primary surgery followed by adjuvant chemotherapy, defined at high risk based on pathological stage) and Stratum B (neoadjuvant chemotherapy followed by surgery without pathological complete response). TILs were centrally assessed on treatment-naive tumor samples (BSL-TILs) and on residual disease after neoadjuvant chemotherapy (RD-TILs, Stratum B). Residual cancer burden (RCB) was assessed in Stratum B. Survival endpoints were: disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS).
RESULTS: BSL-TILs were available for 387 patients, RD-TILs for 330 patients (290 with both BSL-TILs and RD-TILs). Higher BSL-TILs were independently associated with improved outcomes across all endpoints. In Stratum B, higher RD-TILs showed a significant independent association with improved outcomes, outperforming BSL-TILs. RCB was also independently prognostic. Avelumab improved outcomes only for patients with BSL-TILs ≥30%, particularly in Stratum B (3-yr DDFS rates 92.0% vs 58.7%, HR 0.20 in high BSL-TILs and 70.4% vs 70.1%, HR 0.92 in low BSL-TILs, interaction p=0.019). Similar results for DFS and OS. RCB was not predictive for avelumab benefit.
CONCLUSIONS: TILs may predict benefit from adjuvant immunotherapy in early TNBC. These findings warrant validation and support TILs-guided immunotherapy strategies in future trials.
TRIAL REGISTRATION: NCT02926196.

DOI: https://doi.org/10.1158/1078-0432.CCR-26-0975
Cytotherapy. 2026 May 22. pii: S1465-3249(26)00875-3. [Epub ahead of print]28(9): 102914

A 38-color spectral panel for cost efficient characterization of T cell therapy products.

Gage D Paul, Imani A Hall, Patrick J Hanley, Catherine M Bollard, Christopher A Lazarski.

  Investigators must frequently apportion precious sample volumes between multiple assays to measure the viability, potency, and compositional phenotype of cell therapy products and clinical research samples. However, the use of disparate assay modalities may miss critical information which links the expression profile of cells with functional activity, especially when these activated cell populations are rare. To address this shortcoming, we describe in this short report the creation of a 38-color spectral flow cytometry panel for the phenotypic and functional characterization of antigen reactive T cell populations within cellular therapy products and clinical research samples. Our investigations identified that up to 29 potentially co-expressing markers were able to be identified on mixed sample populations using this panel, including phenotype, activation, and exhaustion markers, as well as intracellular cytokine production. Our calculations also highlight spectral flow cytometry is a more efficient use of technician time, reagent cost, and product sample usage as compared with an equivalent set of traditional flow cytometry panels.

Keywords:  T cell immunotherapy; adoptive immunotherapy; cell manufacturing; cost analysis; high parameter flow cytometry; spectral flow cytometry

DOI:  https://doi.org/10.1016/j.jcyt.2026.102914
Clin Cancer Res. 2026 Jul 15.

Spatial Configuration of Pancreatic Cancer Is Associated with Disease Recurrence after Neoadjuvant Therapy and Curative-Intent Resection.

Luis H Cisneros, Merih D Toruner, Zafar Siddiqui, Andrea V Maraone, Miranda Lin, Alexander Xiao, Cornelius Thiels, Mark J Truty, Ben George, Khalid Jazieh, Rob Scheel, Robert R McWilliams, Carlo C Maley, Chris Hartley, Rofyda Elhalaby, Paul Dizona, Qian Shi, Martin E Fernandez-Zapico, Ryan M Carr.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after neoadjuvant therapy (NT) and curative-intent resection. Although major pathologic response predicts favorable outcomes, most patients achieve only minor response with heterogeneous recurrence risk. We asked whether the spatial organization of residual PDAC encodes clinically relevant biology beyond residual tumor burden.
EXPERIMENTAL DESIGN: In a retrospective cohort of 203 resected PDAC patients treated with NT and restricted to minor pathologic response, routine H&E whole-slide images were segmented into cancer and stroma using an AI-enabled pipeline. Spatial composition (patch density, edge density) and configuration (compactness/complexity, intermixing) were quantified and tested associations with disease-free survival (DFS) using multivariable models adjusted for standard clinicopathologic factors.
RESULTS: Shorter DFS was associated with a fragmented, interface-rich tumor-stroma ecology featuring higher edge density and diversity and reduced homotypic aggregation, independent of clinicopathologic variables. Two spatial risk models were independently prognostic: (i) cancer mean shape index plus stromal shape-index variability (adjusted HR 1.71; P=0.003) and (ii) mean stromal patch area plus edge density (adjusted HR 2.19; P=0.002). Both models stratified outcomes where pathologic response grading and residual cancer area did not. High-risk configurations were further associated with reduced intratumoral tumor-infiltrating lymphocyte (TIL) density and infiltration ratio, with relative TIL accumulation at the cancer periphery and within the stroma, consistent with an immune-excluded phenotype.
CONCLUSIONS: Residual cancer-stroma topology quantified from standard H&E slides yields independent prognostic signals after NT in PDAC, provides a cellular immune correlate for spatial risk, and motivates prospective validation and spatially informed adjuvant strategies.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-4968
Immunohorizons. 2026 Jul 10. pii: vlag039. [Epub ahead of print]10(7):

Medium chain fatty acid sensing receptor GPR84 limits antitumor immunity mediated by CD4 T cells in mice.

Anamaria Morales-Alvarez, Timothy A Gilbertson, Hung Nguyen.

  CD4+ T cells play an important role in antitumor immunity due to their capacity to acquire highly functional effector states and cytotoxic-like programs in the tumor microenvironment. However, the mechanisms underlining this process remain largely undefined. Herein, we identify the medium chain fatty acid-sensing receptor GPR84 as a metabolic checkpoint that restricts the antitumor immunity mediated by CD4+ T cells. GPR84 upregulation was detected in tumor-infiltrating CD4+ T cells, and in the absence of GPR84, CD4+ T cells exhibited enhanced tumor control, associated with increase in their proliferation and survival, and with a reprogramming toward a more functionally competent state characterized by increased polyfunctional cytokine production and reduced expression of inhibitory receptors, without accumulation of regulatory T cells. In the tumor antigen-specific mouse model, GPR84 deficiency drastically improved the therapeutic efficacy of adoptively transferred CD4+ T cells. Mechanistically, without GPR84, CD4+ T cells, by upregulating mTORC1 signaling activity, metabolically enhance both glycolysis and mitochondrial activities, thereby gearing toward tumor-killing cytotoxic phenotypes. Importantly, pharmacologic inhibition of GPR84 drastically improves the effectiveness of both PD-1 blockade therapy and adoptive cell transfer. Together, these findings validate GPR84 as a key regulator of CD4+ T-cell metabolic fitness and establish the extracellular lipid sensing pathway as a targetable axis for improving the efficacy and responsiveness of cancer immunotherapies.

Keywords:  GPR84; cancer immunotherapy; cytotoxic CD4+ T cells; immunometabolism; medium chain fatty acids

DOI:  https://doi.org/10.1093/immhor/vlag039
J Immunother Cancer. 2026 Jul 14. pii: e015464. [Epub ahead of print]14(7):

LysoPS-GPR34 axis enhances tumor-associated macrophages efferocytosis to promote immune escape in gastric cancer peritoneal metastasis.

Jialong Lv, Mingyue Zhang, Fan Xiang, Cheng Huang, Dianshi Wang, Kun He, Guanxin Wei, Xiang Chen, Danzeng He, Wenhao Wen, Kaixiong Tao, Chuanqing Wu.

   BACKGROUND: Metabolites sculpt the immunosuppressive tumor microenvironment (TME) that facilitates immune evasion. As a crucial signaling lysophospholipid, lysophosphatidylserine (LysoPS) correlates with advanced disease stages in multiple tumor types. However, the mechanisms by which LysoPS drives gastric cancer peritoneal metastasis remain undefined.
METHODS: Single-cell transcriptomic profiling of primary tumors, normal peritoneum, and metastatic lesions delineated mechanisms underlying LysoPS-mediated tumor-associated macrophages (TAMs) reprogramming. Immunohistochemistry and multiplex immunofluorescence validated GPR34-high TAMs infiltration in peritoneal metastases. Functional validation was performed using molecular assays and in vivo models.
RESULTS: LysoPS accumulated in ascites from patients with gastric cancer peritoneal metastasis, establishing an immunosuppressive TME that drove malignant progression. Using single-cell transcriptome sequencing, we identified a distinct subset of TAMs highly expressing GPR34 enriched in gastric cancer peritoneal metastases, which correlates with tumor progression and immune evasion. Mechanistically, LysoPS engagement of GPR34 activated ERK/c-Jun signaling, transcriptionally upregulating AXL and CD36 to enhance efferocytosis. This effect drove TAMs toward an immunosuppressive phenotype, characterized by enhanced interleukin-10 and transforming growth factor-β secretion. GPR34 inhibitor attenuated M2-like TAMs infiltration while bolstering cytotoxic T cells recruitment and curtailing programmed cell death protein 1 (PD-1)+T cells accumulation. Furthermore, combination with anti-PD-1 therapy synergistically suppressed tumor growth beyond monotherapy efficacy.
CONCLUSIONS: LysoPS-GPR34 axis synergized with efferocytosis to amplify TAMs immunosuppressive properties, fostering an immune-evasive microenvironment; GPR34 inhibitor thus represents a promising strategy to potentiate PD-1 blockade efficacy in gastric cancer peritoneal metastasis.

Keywords:  Gastric Cancer; Immune Checkpoint Inhibitor; Immunosuppression; Macrophage; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2026-015464