bims-tuinly 2026-01-04 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2026–01–04
24 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor Stroma Infiltrating T Cells Predict the Efficacy of Anti-CTLA-4 Antibody in NSCLC.
Interobserver concordance of tumor-infiltrating lymphocyte assessment in triple-negative breast carcinoma; tissue microarray versus whole sections.
Estrogen receptor α expression in tumor-infiltrating lymphocytes from patients with endometrial cancer.
A dual diacylglycerol kinase (DGK) alpha/zeta inhibitor augments the activity of human tumor infiltrating lymphocytes in in vivo and ex vivo models.
Characteristics of CD103+CD8+ T cells in the spleen of Plasmodium yoelii NSM-infected mice.
Multiparametric Detection of Effects of TILs and Oncolytic Virotherapy on Xenograft Mouse Model of Glioblastoma.
Immuno-oncology approaches to overcome T cell exhaustion in melanoma.
Immune cell-based therapies for solid tumors, current challenges and therapeutic advances.
B and T Tumor-Infiltrating Lymphocyte Subtypes According to Subsite: A Colon Cancer Immunophenotyping Map.
Tumor-Infiltrating Lymphocyte Adoptive Cell Therapy With PD-1 Blockade in Pediatric Chemotherapy-Resistant Osteosarcoma.
A Bioorthogonal and Programmable Bacterial Delivery System for Spatiotemporally Targeted Therapy of Solid Tumors.
Implantable artificial lymph node enables rapid in vivo neoantigen-specific T-cell generation and expansion for improving antitumor immunity.
Preclinical assessment of MAGE-A4-specific TCR-NK cells against solid tumors.
The Effect of Perioperative Cimetidine on the Outcomes of Stage 2 Melanoma.
Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.
Age-independent and targetable transcription factor networks regulating CD8+ T cell senescence in aging humans.
Epidermal resident memory T cell fitness requires antigen encounter in the skin.
Engineering IL-21 secretion in T cells using druggable ligand-responsive stabilized domains.
Antigen-specific profiling identifies T-bet+ melanoma-specific CD8+ T cells associated with response to neoadjuvant PD-1 blockade.
DF6215, an α-optimized IL-2-Fc fusion, expands immune effectors and drives robust preclinical anti-tumor activity.
NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control.
Intratumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ cDC1 infiltration and activates anti-tumor immunity.
Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease.
Pan cohort immune biomarker of CD8 lymphocyte activation enabling HGSOC outcome prediction and treatment response.

Anticancer Res. 2026 Jan;46(1): 301-308

Tumor Stroma Infiltrating T Cells Predict the Efficacy of Anti-CTLA-4 Antibody in NSCLC.

Hiroshi Saijo, Yoshihiko Hirohashi, Toshiyuki Sumi, Naoki Shijubo, Astushi Saito, Osamu Honjo, Toyohiro Saikai, Hirotsugu Takabatake, Akihisa Fujita, Yasuhito Honda, Hiroyuki Koba, Hirofumi Chiba, Toshihiko Torigoe.

   BACKGROUND/AIM: Although various therapeutic options are available for advanced or recurrent non-small cell lung cancer (NSCLC), the optimal criteria for selecting combination therapies involving anti-programmed death-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) antibodies with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies remain unclear. Clinical trials suggest potential benefits of the treatment with anti-CTLA-4 antibodies in NSCLC with PD-L1 <1%; however, concerns persist regarding the increased risk of immune-related adverse events (irAEs). Therefore, identifying reliable biomarkers to guide the use of anti-CTLA-4 antibodies is crucial.
PATIENTS AND METHODS: We performed immunohistochemical staining to assess intratumoral tumor-infiltrating lymphocytes (iTILs) and stromal tumor-infiltrating lymphocytes (sTILs) expressing CD8 or FOXP3 using surgically obtained specimens. The association between these cells and the clinical efficacy of the treatment with nivolumab plus ipilimumab was evaluated using univariate and multivariate analyses in NSCLC patients with PD-L1 <1%. Kaplan-Meier analysis was conducted to assess survival outcomes.
RESULTS: Univariate analysis revealed a significant correlation between progression-free survival and sTIL infiltration, but not iTIL infiltration. Patients who responded to therapy exhibited significantly higher CD8+ and lower FOXP3+ iTIL infiltration, as reported previously. Notably, responders also demonstrated significantly higher infiltration of both CD8+ and FOXP3+ sTILs. Moreover, high stromal infiltration of CD8+ T cells was significantly associated with prolonged overall survival, while high FOXP3+ sTILs infiltration showed a trend toward improved overall survival.
CONCLUSION: Despite the increased risk of irAEs, patients with high stromal infiltration of CD8+ and FOXP3+ T cells may derive meaningful clinical benefit from anti-CTLA-4 antibody therapy. Assessing these immune parameters could aid in appropriate patient selection and contribute to optimizing therapeutic outcomes.

Keywords:  NSCLC; Treg; Tumor stroma; anti-CTLA-4 antibody; biomarker

DOI:  https://doi.org/10.21873/anticanres.17944
Cytojournal. 2025 ;22 95

Interobserver concordance of tumor-infiltrating lymphocyte assessment in triple-negative breast carcinoma; tissue microarray versus whole sections.

Maher Sughayer, Fareed Barakat, Elizabeth Sweidan, Bayan Maraqa, Ahmad Alsughayer.

   Objective: Tumor-infiltrating lymphocyte (TIL) assessment is recognized as an important prognostic and therapeutic biomarker in several tumors, including triple-negative breast cancer (TNBC). TILs face several challenges, including low to intermediate interobserver concordance. The use of tissue microarray (TMA) in TIL assessment and its relationship/concordance with whole sections (WS) has been studied only rarely. The aim of this study is to evaluate the reproducibility of TIL assessment in TNBC among various users and to compare TIL assessment using TMA versus whole tissue sections (WS).
Material and Methods: Hematoxylin and eosin-stained sections of TMAs were prepared and assessed for quality and adequacy. Corresponding WS slides for all cases were retrieved and independently scored for TILs by one junior and two senior pathologists. The assessment followed the guidelines of the International TILs Working Group. TIL scores were categorized into three groups: Low: <20%; intermediate: 20-49%; and high: ≥50%. A total of 100 cases were collected; however, 76 cases were evaluable after excluding inadequate samples or cases with missing information.
Results: Fleiss' kappa was used to assess interobserver agreement among the three raters for both WS and TMA datasets. The Intraclass Correlation Coefficient (ICC) was used to assess the degree of agreement among the three raters for continuous variables before categorization, and Cohen's kappa was applied to both WS and TMA datasets to assess interobserver agreement between any two raters. The interobserver agreement for WS analysis (Cohen's kappa) was fair, while for TMA, it was moderate. The ICC also showed moderate agreement. Cohen's kappa for TMA versus WS for each of the three observers ranged from fair to strong. Fleiss' kappa showed fair agreement for WS versus TMA.
Conclusion: Interobserver variability in TIL scoring remains a challenge. TMAs improve consistency but at the cost of reduced correlation with WS assessments.

Keywords:  Breast carcinoma; Concordance; Tissue microarray; Triple-negative; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.25259/Cytojournal_116_2025
Oncol Lett. 2026 Feb;31(2): 83

Estrogen receptor α expression in tumor-infiltrating lymphocytes from patients with endometrial cancer.

Marcin A Jedryka, Anna Slawek, Paulina Kubik, Daria Lorek, Anna Ewa Kedzierska, Andrzej Czekanski, Rafał Matkowski, Anna Chelmonska-Soyta.

  The complex crosstalk between the tumor milieu, including the hormonal environment and immune system interactions, is important to tumor growth in endometrial cancer (EC). Estradiol-mediated estrogen receptor α (ERα) signaling is critical for the function of regulatory tumor-infiltrating lymphocytes (TILs) in patients with cervical cancer. Therefore, the present study investigated the relative ERα level in infiltrating lymphocytes derived from EC tissues and whether its variable expression is associated with clinicopathological features, including the molecular classification. Endometrial tumor and normal endometrium samples were collected from 82 patients diagnosed with EC; however, only 54 samples were assessed as sufficient and qualified for further study. The frequency of T helper lymphocytes (Th cells), cytotoxic T lymphocytes (CTLs) and B lymphocytes (B cells) as well as the percentages of these cells expressing ERα were examined using flow cytometry. Furthermore, the expression of ERα in these TIL subpopulations was evaluated using median fluorescence intensity (MFI) to assess the absolute level of ERα in the studied lymphocytes. Associations of ERα levels in TILs with clinicopathological characteristics, including molecular subtypes, were measured. All the studied TIL subpopulations showed a significantly lower ERα level compared with normal endometrial tissue, which constituted the control group. However, the frequencies of Th cells and Th cells expressing ERα were significantly increased, while the frequencies of CTLs and CTLs expressing ERα were significantly decreased in EC compared with the control. The frequency of B cells expressing ERα was significantly increased in high grade EC tumors and tumors harboring mismatch repair deficiency. ERα expression (demonstrated with MFI) on examined TIL subsets was negatively correlated with body mass index in patients but did not demonstrate other correlations with the examined clinicopathological prognostic factors. The mechanism of ERα decrease in TILs from endometrial tumors as well as its prognostic significance and potential role in therapeutic targeting needs further investigation, including further examination of its molecular background and functional validation experiments.

Keywords:  The Cancer Genome Atlas; endometrial cancer; estrogen receptor α; median fluorescence intensity; molecular clusters; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3892/ol.2025.15436
Oncoimmunology. 2026 Dec 31. 15(1): 2608439

A dual diacylglycerol kinase (DGK) alpha/zeta inhibitor augments the activity of human tumor infiltrating lymphocytes in in vivo and ex vivo models.

Phurin Areesawangkit, Karen Pei-Yi Fong, Emma Niemeyer, Yan Li, Kelly Markowitz, Devora Delman, Ryan Krause, Justine Carl, Pat Feldman, Lisa Troung, Rodrigo Hess, Xiaodi Ren, Cynthia Timmers, Sunkyu Kim, Robert Brody, Sunil Singhal, Jarrod Predina, Evgeniy Eruslanov, Gregory Beatty, Bihui Melidosian, Steven M Albelda.

  Endogenous or adoptively transferred tumor-infiltrating lymphocytes (TILs) often lose their functional capacity due to the activation of intrinsic inhibitory pathways, which then limits their ability to control tumor growth. In this study, we examined the effects of blocking a key intracellular inhibitory enzyme, diacylglycerol kinase (DGK) in human T cells, using a novel inhibitor (DGKi) called INCB165451 that blocks both DGKα and DGKζ, the two primary DGK isoenzymes that negatively regulate T cells through the diacylglycerol (DAG) signaling pathway. We first evaluated the effects of the DGKi in enhancing the efficacy of adoptive human T cell transfer in a non-small cell lung cancer (NSCLC) mouse model and found that the DGKi significantly potentiated anti-tumor efficacy through multiple mechanisms, including increased intratumoral T cell infiltration, upregulation of genes associated with inflammatory responses, and reduction of TIL hypofunction, as evidenced by enhanced cytokine production following ex vivo anti-CD3 antibody stimulation. We next studied the effects of the DGKi on human TILs derived from tumor digests or studied in situ in precision-cut tumor slices of both head and neck cancer and NSCLC patient samples. After stimulation of the TILs with anti-CD3 antibodies, we found that the DGKi enhanced gene and protein expression of proinflammatory cytokines and chemokines. Finally, we demonstrated that the DGKi could augment T cell activation in human tumor slices that were stimulated by an anti-EGFR/anti-CD3 bispecific T cell engager (BiTE). These data demonstrate strong activity of the DGKi in human TILs and highlight promising potential avenues for clinical translation.

Keywords:  T cell hypofunction; T cells; adoptive T cell transfer; diacylglycerol kinase; diacylglycerol kinase inhibitor; head and neck cancer; lung cancer; precision-cut tumor slices; tumor digest; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1080/2162402X.2025.2608439
Front Cell Infect Microbiol. 2025 ;15 1668438

Characteristics of CD103+CD8+ T cells in the spleen of Plasmodium yoelii NSM-infected mice.

Xingfei Pan, Feihu Shi, Shanni Tang, Meilin Liu, Li Pan, Guikuan Liang, Lu Li, Hongyan Xie, Shan Zhao, Jun Huang.

   Background: CD8+ T cells play a critical role in controlling Plasmodium infection. CD103, an integrin composed of αE and β7 subunits, is widely recognized as a cell surface marker for tissue-resident memory T (TRM) cells and tumor-infiltrating lymphocytes (TILs).
Methods: In this study, a Plasmodium infection model was constructed by intraperitoneally injecting 106 infected red blood cells (iRBCs) into C57BL/6 mice. CD45+ cells in the spleen of naïve and infected mice were sorted and subjected to single-cell RNA sequencing (scRNA-seq). The content, activation, and function of CD103+CD8+ T cells were detected using flow cytometry. qPCR and dual-luciferase reporter assays were performed to find the key transcription factor.
Results: Here, we identified a substantial subset of CD103+CD8+ T cells in the spleen of naïve mice, whose proportion and count declined rapidly following Plasmodium yoelii NSM infection. Compared to CD103-CD8+ T cells, in both naïve and infected mice, CD103+CD8+ T cells exhibited higher CD62L expression and lower levels of CD44, CD69, and TIGIT, and they rarely secreted IFN-γ or granzyme B upon PMA plus Ionomycin (PI) stimulation. Single-cell RNA sequencing revealed that differentially expressed genes (DEGs) were enriched in pathways related to "cytoplasmic translation" and "ribosome biosynthesis", suggesting that these cells are in a pre-activation preparatory state. Bioinformatics predictions and dual-luciferase reporter assays indicated that the transcription factor LEF1 may regulate Itgae transcription by binding to its promoter sequence.
Conclusions: Collectively, our findings demonstrate that splenic CD103+CD8+ T cells express fewer activation and function-associated molecules, which may contribute to their limited role in the course of P. yoelii NSM infection in C57BL/6 mice, and implicates LEF1 in the regulation of CD103 expression.

Keywords:  CD103; CD8 T cells; LEF1; Plasmodium yoelii; spleen

DOI:  https://doi.org/10.3389/fcimb.2025.1668438
Biomedicines. 2025 Dec 04. pii: 2977. [Epub ahead of print]13(12):

Multiparametric Detection of Effects of TILs and Oncolytic Virotherapy on Xenograft Mouse Model of Glioblastoma.

Gaukhar M Yusubalieva, Daria A Chudakova, Polina G Shirokikh, Diana V Yuzhakova, Elena B Kiseleva, Daria A Sachkova, Varvara V Dudenkova, Daria P Kirsova, Maria S Myzina, Elvira P Yanysheva, Alexander V Panov, Natalia F Zakirova, Anastasia V Poteryakhina, Alexander S Semikhin, Alexander A Kalinkin, Vladimir P Baklaushev.

  Background/Objectives: Glioblastoma (GBM) is an aggressive primary brain tumor with dismal prognosis and limited treatment options. Immunotherapy, including personalized approaches using tumor-infiltrating lymphocytes (TILs) and allogeneic natural (NK) or engineered killer cells (chimeric antigen receptor NK, NK-CAR), and oncolytic viruses (OV), has shown some potential in GBM. Combining different therapeutic strategies may enhance treatment efficacy. Here, we present a xenograft GBM mouse model with multiparametric detection for various immunotherapy research applications. Methods: In a xenograft GBM NOD-Prkdcs scid Il2rgem1/Smoc (NSG) mouse model based on orthotopic transplantation of patient-derived GBM cultures retaining tumor heterogeneity, intravenous and intratumor immunotherapeutic interventions by TIL and OV therapy were performed. Xenograft engraftment was evaluated using intravital MRI; delivery of OV and TILs to the tumor and changes in the tumor and peritumoral space were assessed using intravital confocal microscopy; and metabolic and structural changes in the tumor and peritumoral environment were assessed via fluorescence lifetime imaging microscopy (FLIM) and optical coherence tomography (OCT). The intravital imaging data were compared with the results of preliminary and final histological and immunocytochemical data. Results: Both OV and TILs demonstrated tumor-specific targeting and delivery across the blood-brain barrier. Further, we showed that in this model the xenograft response to both therapeutic treatments can be assessed using FLIM and OCT. Conclusions: Overall, this work presents an optimized mouse model suitable for assessing the effect of combined TIL immunotherapy and OV on GBM in translational studies.

Keywords:  Fluorescence lifetime imaging microscopy (FLIM); TILs; animal models; cell therapy; glioblastoma; immunotherapy; oncolytic viruses; optical coherence tomography (OCT)

DOI:  https://doi.org/10.3390/biomedicines13122977
Semin Oncol. 2025 Dec 02. pii: S0093-7754(25)00146-0. [Epub ahead of print]53(1): 152454

Immuno-oncology approaches to overcome T cell exhaustion in melanoma.

Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mohammad Y Alshahrani, Muzdalifa Mejbel Fedwi, Subbulakshmi Ganesan, Zahraa Abbas Al-Khafaji, Vimal Arora, Amrita Pal, Priya Priyadarshini Nayak, Sarvar Islomov, Chou-Yi Hsu.

  Melanoma, a highly aggressive type of skin cancer, has undergone incredible developments in immunotherapy, particularly in modulating T-cell immunity. T cells are essential components of the antitumor immune response and can undoubtedly influence the effectiveness of melanoma treatment. This review will evaluate the roles of the different T cell subsets (CD8+, CD4+, and Tregs) in melanoma immunity. CD8+ T cells are important effectors, as they primarily recognize and kill tumor cells. However, CD8+ T cells are often dysfunctional due to exhaustion driven by chronic antigen exposure and dysfunctional immune checkpoint pathways, specifically PD-1 and CTLA-4. On the other hand, CD4+ T cells, also known as T helper cells, play a crucial role in coordinating both pro- and antitumor immune responses. In contrast to T cells, Tregs, which are often present in the tumor microenvironment, lead to immune suppression through their activity, limiting T cell activity. This review will also examine the mechanisms of T-cell exhaustion, metabolic reprogramming within the tumor microenvironment (TME) of T-cell subsets, and the role of immune checkpoint pathways, such as CTLA-4 and PD-1, in T-cell immunity. Adoptive cell therapies (ACT), specifically Tumor-Infiltrating Lymphocyte (TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy, have shown the ability to rejuvenate T-cells to enhance clinical outcomes. However, several resistance mechanisms and the suppressive TME presents difficulties. Future efforts will focus on combination therapies, metabolic interventions, and novel engineering techniques to overcome barriers to T-cell function exhaustion and T-cell persistence. Evaluating biomarkers associated with early prediction for therapeutic benefit and associated toxicity is important for personalizing a particular treatment. Ultimately, this review highlights the potential of targeting T-cell exhaustion to enhance the effectiveness of T-cell-based therapies in improving outcomes for melanoma patients.

Keywords:  Exhaustion; Immunity; Immunotherapy; Melanoma; T cell

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152454
Cell Commun Signal. 2025 Dec 31.

Immune cell-based therapies for solid tumors, current challenges and therapeutic advances.

Shukoofeh Torabi, Elham Yekzaman, Soroush Taherkhani, Negin Talachi, Roya Khoshravesh, Arezoo Khosravi, Mahsa Salehi, Ali Zarrabi, Massoud Vosough.

  Solid tumors remain difficult to treat due to antigen heterogeneity, physical barriers that limit immune-cell trafficking, and a profoundly immunosuppressive tumor microenvironment (TME). Over the past decade, cancer immunotherapy advanced considerably through innovative strategies, including macrophage reprogramming and CAR-macrophages, dendritic-cell (DC) vaccines, natural killer (NK) and natural killer T (NKT) cell approaches, tumor-infiltrating lymphocyte (TIL) therapy, TCR-engineered and CAR-T cells, emerging B-cell engineering, and cell-derived extracellular vesicles (EVs). Here we summarize how each modality interacts with the TME, highlight key clinical milestones (e.g., FDA approval of a TIL product for melanoma in 2024), and outline bioengineering strategies-multi-antigen targeting, cytokine armoring, trafficking cues, and safety switches-that aim to overcome resistance and toxicity. We also review EV-based, cell-free strategies that retain tumor specificity with potentially improved safety and manufacturability. Finally, we discuss remaining barriers-standardized manufacturing, on-target/off-tumor effects, limited persistence-and propose rational combinations with checkpoint blockade, radiotherapy, and targeted agents. This overview positions immune cell-based therapy as a rapidly maturing, transformative approach for solid tumors.

Keywords:  Cell therapy; Extracellular vesicles; Immune therapy; Solid tumor; TME

DOI:  https://doi.org/10.1186/s12964-025-02632-y
Biomedicines. 2025 Nov 23. pii: 2856. [Epub ahead of print]13(12):

B and T Tumor-Infiltrating Lymphocyte Subtypes According to Subsite: A Colon Cancer Immunophenotyping Map.

Giorgiana Fagarasan, Bogdan Alexandru Gheban, Vlad Fagarasan, Doinita Crisan, Teodora Telecan, Vasile Virgil Bintintan, Radu Ioan Seicean, Alexandra Caziuc, George Calin Dindelegan.

  Background: Accumulating evidence regarding the association between tumor-infiltrating lymphocyte (TIL) subtypes and prognosis in colorectal cancer has emerged recently in the literature. Whether the prognostic impact of TIL subsets is different according to tumor location remains unknown, despite genetic, epigenetic and molecular differences between the proximal and distal colon. Our study aimed to investigate the value of CD3+ lymphocytes, reflecting overall T-cell infiltration, CD8+ cells identifying cytotoxic effector T-cells and CD73+ cells acting as a modulator of immunosuppression, stratified by primary tumor location. Methods: The density of CD73+, CD3+ and CD8+ tumor-infiltrating B- and T-cells was determined in colon cancer patients using whole-section tissue sampling, heat-induced epitope retrieval, primary antibodies and DAB visualization. QuPath Cell counter function quantified nucleated cells and immune-positive percentages; ImageJ assessed staining intensity via color deconvolution and optical density. An Immunoreactive Score combined intensity and positivity for immune profiling. The Receiver Operating Characteristic (ROC) curve analysis was used to determine the optimal cut-off values for CD3+, CD8+ and CD73+ lymphocytes. Statistical analysis was performed in order to identify potential associations between TILs expression and pathological characteristics, according to the location of the primary tumor. Survival analysis was carried out using the Kaplan-Meier method. Results: A total of 100 patients were included in the study. CD3+ T-cells were the most abundantly expressed and were more predominantly encountered in the right colon. Total CD3+ numbers were correlated with T stage and the presence of perineural invasion in left-sided tumors, as well as with tumor grading in the right colon. Correlation analysis based on CD3+ threshold values according to tumor location demonstrated a statistically significant association between a higher N stage and low CD3+ cell values (p value = 0.0306), and higher perineural invasion and low CD3+ TILs values in the left colon (p value = 0.0123). In addition, low CD8+ values were associated with a higher T stage in the left colon (p value = 0.0382). Survival analysis did not demonstrate statistically significant differences between the investigated groups. Conclusions: TIL subtypes in colon cancer patients demonstrate significant variability according to the location of the primary tumor and are associated with different clinical and pathological characteristics. This exploratory study requires larger validation before TIL densities can guide therapy.

Keywords:  colon cancer; location; tumor-infiltrating B-lymphocytes; tumor-infiltrating T-lymphocytes

DOI:  https://doi.org/10.3390/biomedicines13122856
Pediatr Blood Cancer. 2025 Dec 29. e70091

Tumor-Infiltrating Lymphocyte Adoptive Cell Therapy With PD-1 Blockade in Pediatric Chemotherapy-Resistant Osteosarcoma.

Helen Thut, Reto Ritschard, Katharina Glatz, Raphael N Vuille-Dit-Bille, Maya C Andre, Stephanie J Gros, Severin Kasser, Andreas H Krieg, Renata Rosa Pereira, Fatime Krasniqi, Heinz Läubli, Alexandra Schifferli.

DOI: https://doi.org/10.1002/1545-5017.70091
Exploration (Beijing). 2025 Dec;5(6): 20240396

A Bioorthogonal and Programmable Bacterial Delivery System for Spatiotemporally Targeted Therapy of Solid Tumors.

Yu-Jia Wang, Wen-Jie Jiang, Hua-Jun Zhao, Jian-Qun Deng, Yi-Min Cai, Yi Li, Xiao-Lin Meng, Jin Hou, Feng-Shan Wang, Ju-Zheng Sheng.

  Rapid advances in synthetic biology are driving the development of microbes as therapeutic agents. While the immunosuppressive tumor microenvironment creates a favorable niche for the systematic delivery of bacteria and therapeutic payloads, these can be harmful if released into healthy tissues. To address this limitation, we designed a spatiotemporal targeting system for engineered Escherichia coli Nissle 1917, controlled by azide-modified hyaluronic acid hydrogel and near-infrared radiation induction. Using a temperature-driven genetic status switch, the system produced durable therapeutic output and promoted the therapeutic activity in solid tumors. The combination of azide-modified hyaluronic acid hydrogel and temperature-sensitive, engineered Escherichia coli Nissle 1917 provided spatiotemporal targeting of solid tumors, not only showing significant therapeutic effects on primary solid tumors, but also inhibiting the metastasis and recurrence of cancer cells by enhancing tumor-infiltrating lymphocytes. This system has potential for clinical application.

Keywords:  bioengineered hydrogels; long‐term antitumor protection; spatiotemporal localization of therapeutic bacteria

DOI:  https://doi.org/10.1002/EXP.20240396
J Immunother Cancer. 2025 Dec 31. pii: e013043. [Epub ahead of print]13(12):

Implantable artificial lymph node enables rapid in vivo neoantigen-specific T-cell generation and expansion for improving antitumor immunity.

Zhixiong Cai, Kongying Lin, Xiuqing Dong, Zhenli Li, Geng Chen, Luobin Guo, Pan Mou, Peizhe Chen, Junjing Huang, Ling Li, Xiaolong Liu, Ruijing Tang, Yongyi Zeng.

   BACKGROUND: Tumor neoantigen vaccines typically require multiple prime-boost immunizations over several weeks or even months to elicit sufficient neoantigen-specific T-cell responses, which greatly limits their effectiveness against rapidly progressing cancers, such as hepatocellular carcinoma.
METHODS: Here, we developed a functionalized alginate scaffold for T-cell activation as an artificial lymph node (FAST-LN) to rapidly and efficiently generate tumor neoantigen-specific T cells in vivo. The FAST-LN consists of an alginate scaffold crosslinked with calcium ions and hyaluronic acids conjugated with anti-TIM-3 (T cell immunoglobulin and mucin domain-containing protein-3) antibodies, then incorporates tumor neoantigen-encoding adenoviral vaccines, dendritic cells (DCs), and various cytokines (C-C motif chemokine ligand 21 (CCL21), interleukin (IL)-2, IL-4, and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)) that maintain DC maturation and recruit T cells for antigen presentation.
RESULTS: This design facilitates efficient DC-T cell interactions within FAST-LN, enabling rapid generation of neoantigen-specific T cells for antitumor responses. In vivo antitumor studies demonstrated superior therapeutic efficacy of FAST-LN over traditional vaccines in mouse tumor models. Mechanistically, FAST-LN significantly enhanced tumor infiltration of CD8+ T cells, Th1 cells and macrophages, orchestrating robust antitumor responses.
CONCLUSIONS: Our results demonstrate that implantable FAST-LN rapidly induces tumor neoantigen-specific T cells in vivo, offering a promising strategy for neoantigen-based cancer immunotherapy.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Solid tumor; T cell; Vaccine

DOI:  https://doi.org/10.1136/jitc-2025-013043
Immunother Adv. 2026 ;6(1): ltaf036

Preclinical assessment of MAGE-A4-specific TCR-NK cells against solid tumors.

Margherita Boieri, Justyna Kmiecik, Maja Sandve, Zara Hannoun, Martha Eimstad Haugstøyl, Inês Cardoso, Sarah Vollmers, Anja Ruppelt Oldenburg, Luz Maria Mora-Velandia, Camilla Sletten, Giulia Malachin, Artur Cieslar-Pobuda, Liliane Christ, Pimthanya Wanichawan, Dennis Clement, Michelle Lu Saetersmoen, Frida Loe Haugen, Amanda Malene Ruud, Julia Mayumi Ino, Pranav Oberoi, Anders Holm, Emilie Gauthy, Namir Jafar Hassan, Sylvie Pollmann, Luise Ullrike Weigand.

  T cell (Tc) receptor (TCR)-based cell therapies have shown clinical efficacy across many cancer types and represent an attractive strategy for targeting solid tumors. However, the immunosuppressive tumor microenvironment, downregulation of target antigen and HLA, and the need for an autologous source limit the efficacy and the accessibility of TCR-Tc therapies. Early clinical trials have shown the potential of natural killer cells (NKs) as a therapy to treat hematological and solid cancers. Allogeneic NKs, engineered to express a TCR, represent a novel and promising strategy overcoming the limitations of T and NKs therapies. Here we describe the development of a product consisting of NKs engineered to express an affinity-enhanced TCR recognizing MAGE-A4, a clinically validated tumor antigen expressed across several solid tumors. The introduction of the TCR does not disrupt the innate functionality of NKs and adds TCR-mediated specific killing of antigen-positive targets. In fact, the innate potential of the NKs appears to be enhanced by the presence of the CD3-TCR complex, creating NKs with increased potency. TCR-NKs are faster, more potent than TCR-Tc and retain killing activity in the absence of TCR target antigen thus potentially overcoming tumor heterogeneity and/or antigen loss. Lastly, TCR-NKs are not activated when co-cultured with normal cells, displaying a safe profile. Combining the innate cytotoxicity of NKs with MAGE-A4-specific targeting of an affinity-enhanced TCR, results in a potent and safe cellular product representing a promising and novel therapeutic off-the-shelf paradigm for the treatment of many solid cancers.

Keywords:  MAGE-A4; TCR-NK cells; affinity enhancement; immunotherapy; solid tumors

DOI:  https://doi.org/10.1093/immadv/ltaf036
South Asian J Cancer. 2025 Oct;14(4): 851-854

The Effect of Perioperative Cimetidine on the Outcomes of Stage 2 Melanoma.

Falah Abu Hassan, Mohanad Al Obaidi, Yasir Al-Hilli, Ola Al-Jobory, Ahmad Hallak, Kate Holder, Basheer Mohammed, Lusine Nahapetyan, Waqas Rasheed, Yousuf Tawfeeq, Stephen E Wright.

   Objectives: The use of immunotherapies in the treatment of melanoma has significantly improved the survival of patients with advanced disease. Historically, histamine has been implicated in the pathogenesis of several cancers. Cimetidine does play a role in modulating the immune system and was advocated as an immunotherapeutic agent since the 1970s. Cimetidine has been showing promise in conjunction with standard care in many cancers in vitro and in vivo. However, its effects in melanoma have not been explored yet. Our study was designed to determine if cimetidine taken in the perioperative period improves the disease-free survival (DFS) or overall survival in patients with the American Joint Committee on Cancer, seventh edition (AJCC 7) stage 2 melanoma.
Materials and Methods: We have reviewed all the patients with stage 2 melanoma in our center in a retrospective cohort to assess the difference in survival between patients who received H2 blockers in the perioperative period and those who did not.
Statistical Analysis and Results: Thirty-two patients were included in the analysis. Nine of 32 patients received H2 blockers in the perioperative period. All the patients were males except for one female in the control group (4.3%). The age in the analyzed population ranged between 51 and 92 years; the median age was 70 years (mean: 71; standard deviation: 10). The median overall survival of the patients who received H2 blockers was 112.7 months and it was 77.2 months for those who did not receive H2 blockers. There was no difference in DFS between the two groups ( p = 0.5395), and there was no difference in the overall survival ( p = 0.4770). The cumulative dose was strongly correlated with the overall survival in the patients who received H2 blockers ( r = 0.8341, p = 0.0196).
Conclusion: Despite having a small treatment group, we were able to detect a strong correlation between the cumulative dose of H2 blockers received and the overall survival.

Keywords:  cancer; cimetidine; immunotherapy; melanoma; stage 2

DOI:  https://doi.org/10.1055/s-0044-1790542
Pharmaceutics. 2025 Nov 26. pii: 1520. [Epub ahead of print]17(12):

Rewiring T Cell Metabolism to Enhance CAR T Cell Function in Solid Tumor Microenvironments.

Alex Wade Song, Xiaotong Song.

  Background/Objectives: Chimeric antigen receptor (CAR) T cells have shown remarkable clinical success in certain blood cancers but remain largely ineffective in solid tumors. A major reason for this limitation is the hostile tumor microenvironment, which restricts oxygen and nutrients while producing toxic metabolites that suppress immune cell activity. This review aims to examine how targeted metabolic reprogramming can overcome these barriers and improve CAR T cell performance. Methods: We evaluated preclinical and translational studies that focused on engineering CAR T cells to resist hypoxia, improve nutrient utilization, reduce metabolic exhaustion, and counteract suppressive metabolites in solid tumors. Results: Emerging strategies include engineering resistance to low oxygen and high lactate, enhancing nutrient uptake through transporter overexpression, and blocking inhibitory pathways such as those driven by adenosine. These approaches improve CAR T cell persistence, memory formation, and cytotoxic function in challenging tumor environments. Conclusions: Integrating metabolic reprogramming with conventional CAR design is essential to unlock the full potential of CAR T therapy against solid tumors. Continued innovation in this area will be critical for translating laboratory advances into effective clinical treatments.

Keywords:  CAR T cells; adenosine; hypoxia; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics17121520
Cell Rep. 2025 Dec 31. pii: S2211-1247(25)01567-0. [Epub ahead of print]45(1): 116795

Age-independent and targetable transcription factor networks regulating CD8+ T cell senescence in aging humans.

Paolo S Turano, Elizabeth Akbulut, Hannah K Dewald, Themistoklis Vasilopoulos, Patricia Fitzgerald-Bocarsly, Utz Herbig, Ricardo Iván Martínez-Zamudio.

  The age-related decline in immunity is accompanied by the accumulation of senescent CD8+ T cells. Using senescent cell isolation coupled with multi-omics profiling, we reveal the transition to senescence to be controlled by chromatin state-specific transcription factor (TF) networks in younger and older donors independent of age. These TF networks mediate widespread enhancer remodeling, repressing cell identity genes while upregulating inflammatory and secretory pathways. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8+ T cells. Senescent CD8+ T cell gene signatures also predict responsiveness to chimeric antigen receptor (CAR)-T cell therapy in diffuse large B cell lymphomas. Overall, our study defines the gene-regulatory mechanisms underlying human CD8+ T cell senescence, highlights TF network perturbation as a viable strategy to manipulate the senescence state, and identifies senescent CD8+ T cell gene signatures as prognostic tools for immunotherapy outcome.

Keywords:  CAR-T cell; CD8(+) T cells; CP: Immunology; CP: Molecular biology; aging; cellular senescence; chromatin; immunosenescence; immunotherapy; inflammaging; inflammation; transcription factor networks

DOI:  https://doi.org/10.1016/j.celrep.2025.116795
Elife. 2025 Dec 30. pii: RP107096. [Epub ahead of print]14

Epidermal resident memory T cell fitness requires antigen encounter in the skin.

ImmGen Consortium OpenSource T cell Project

  CD8+ tissue-resident memory T cells (TRM) develop from effectors that seed peripheral tissues where they persist providing defense against subsequent challenges. TRM persistence requires autocrine TGFβ transactivated by integrins expressed on keratinocytes. TRM precursors that encounter antigen in the epidermis during development outcompete bystander TRM for TGFβ resulting in enhanced persistence. ScRNA-seq analysis of epidermal TRM revealed that local antigen experience in the skin resulted in an enhanced differentiation signature in comparison with bystanders. Upon recall, TRM displayed greater proliferation dictated by affinity of antigen experienced during epidermal development. Finally, local antigen experienced TRM differentially expressed TGFβRIII, which increases avidity of the TGFβRI/II receptor complex for TGFβ. Selective ablation of Tgfbr3 reduced local antigen experienced TRM capacity to persist, rendering them phenotypically like bystander TRM. Thus, antigen-driven TCR signaling in the epidermis during TRM differentiation results in a lower TGFβ requirement for persistence and increased proliferative capacity that together enhance epidermal TRM fitness.

Keywords:  cd8; epidermis; immunology; inflammation; mouse; resident memory T cells; skin; tgfb

DOI:  https://doi.org/10.7554/eLife.107096
Sci Rep. 2025 Dec 27.

Engineering IL-21 secretion in T cells using druggable ligand-responsive stabilized domains.

Dong Hyun Kim, Seo Jin Lee, Taeyoung Ahn, Hyung-Young Kim, Kyungsu Kim, Hyungseok Seo.

  Cytokine-based immunotherapies face challenges due to systemic toxicity and uncontrolled cytokine release. To enable precise control, we developed a druggable ligand-dependent IL-21 secretion system using destabilization domains (DDs). ER50 and DHFR facilitated ligand-responsive IL-21 secretion, with ER50 providing the most sustained regulation. Structural analysis revealed that N-terminal fusion improved IL-21 receptor binding, while C-terminal fusion weakened interactions. In primary T cells, IL-21 secretion promoted T stem-like (Tscm) cell differentiation, enhancing persistence for adoptive cell therapy. This system enables reversible, tunable cytokine control, offering a safer and more flexible approach for engineered T cell therapies.

Keywords:  Destabilization domain (DD); IL-21; Immunotherapy; Ligand-dependent regulation; T cell engineering

DOI:  https://doi.org/10.1038/s41598-025-32677-5
Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00538-0. [Epub ahead of print]

Antigen-specific profiling identifies T-bet+ melanoma-specific CD8+ T cells associated with response to neoadjuvant PD-1 blockade.

Guanning Wang, Daniel Yoon, Ajeya Nandi, Khushboo Patel, Tarek Azar, Justin Kim, Nicholas A Han, Aaron Nickie, Stella Park, Kevin Wang, Patrick Yan, Shraya Divaker, Jennifer Tabita-Martinez, Lydia Giles, Mary Carberry, Jean Christophe Beltra, Mark M Painter, Cecile Alanio, Ravi K Amaravadi, Lynn M Schuchter, Beatriz M Carreno, Gerald P Linette, David E Elder, Robert M Brody, Phyllis Gimotty, John T Miura, Giorgos C Karakousis, Xiaowei Xu, Tara C Mitchell, Alexander C Huang.

  Despite widespread immune profiling in cancer immunotherapy, the antigen-specific responses that drive clinical outcomes remain poorly defined. In a prospective neoadjuvant trial (NCT04013854) of a single-dose anti-PD-1 (nivolumab) in stage III melanoma, we performed antigen-specific profiling of melanoma and viral-specific CD8+ T cells across blood, tumor, and lymph node compartments. Using combinatorial tetramers, we detected melanoma-specific CD8+ T cells in 72% of HLA-A1, -A2, and -A3 patients. These cells displayed distinct phenotypes shaped by tissue and antigen context. Tumor-infiltrating T-bet+ intermediate exhausted CD8+ T cells were strongly associated with pathologic response, while CD39+ terminal exhausted cells marked non-response. T-bet and CD39 expression also stratified responses in uninvolved lymph nodes, suggesting early divergence of therapeutic immune trajectories. Longitudinal profiling revealed that circulating melanoma-specific CD8+ T cell dynamics was antigen-dependent and associated with clinical outcomes. Our findings highlight the clinical value of antigen-specific profiling and identify mechanistic correlates of anti-PD-1 efficacy.

Keywords:  CD8 T cell reinvigoration; PD-1 blockade; antigen-specific CD8 T cells; biomarker; exhausted T cells; exhausted subsets; immune checkpoint; immune profiling; lymph node; neoadjuvant

DOI:  https://doi.org/10.1016/j.ccell.2025.12.004
Cell Rep Med. 2025 Dec 29. pii: S2666-3791(25)00591-9. [Epub ahead of print] 102518

DF6215, an α-optimized IL-2-Fc fusion, expands immune effectors and drives robust preclinical anti-tumor activity.

Adam P Stockmann, Sylvia Vincent, Lauren Herschelman, Ching-Shin Huang, Jingya Ma, Daniel Fallon, Patrick Kirby, Eva Gutierrez, Danielle Talbot, Stuart W Hicks, Nicolai Wagtmann, Ann F Cheung.

  DF6215 is a rationally engineered interleukin-2 (IL-2) Fc-fusion protein developed to overcome efficacy and safety limitations of traditional IL-2 cancer immunotherapy. Unlike non-alpha (non-α) IL-2 variants that eliminate CD25 binding and underperform clinically, DF6215 retains moderate IL-2 receptor α (IL-2Rα) affinity while enhancing IL-2Rβγ signaling and extending the half-life via an engineered immunoglobulin (Ig)G1 Fc domain. This design preferentially expands cytotoxic CD8+ T cells and natural killer cells over regulatory T cells, resulting in favorable effector-to-regulatory cell ratios, enhanced immune activation, and robust tumor regression in mouse models. In poorly immunogenic tumors, DF6215 synergized with PD-1 blockade to achieve durable responses without added toxicity. Cynomolgus monkey studies confirm DF6215's pharmacodynamics and favorable safety profile, with no signs of vascular leak syndrome or cytokine release syndrome. These findings position DF6215 as a differentiated IL-2 capable of modulating the tumor microenvironment and achieving potent anti-tumor immunity with improved tolerability, supporting its advancement into clinical trials for solid tumors.

Keywords:  DF6215; Fc fusion; IL-2; cancer immunotherapy; engineered cytokine

DOI:  https://doi.org/10.1016/j.xcrm.2025.102518
bioRxiv. 2025 Dec 15. pii: 2025.12.11.693768. [Epub ahead of print]

NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control.

W Sam Nutt, Mitchell G Kluesner, Emma Bingham, Ekram Gad, Dani Miller, Victor Zepeda, Andrew J Snyder, Sydney A Marsh, Shannon M Liudahl, Mari Hoffman, Lillian LeBlanc, Madeleine E Volfbeyn, Sarah M Garrison, Megha Sarvothama, Kevin C Barry, Mark B Headley, Mario Marcondes, Shivani Srivastava.

CAR-T cells have yet to show widespread efficacy in solid tumors due in part to their poor persistence and loss of function in the tumor microenvironment. Further, heterogenous expression of most CAR target antigens in solid tumors can lead to escape of antigen-null tumors that resist CAR-T killing. Strategies to cooperatively boost both CAR-T and endogenous anti-tumor immunity could curb tumor escape and may be critical for achieving durable efficacy in cancer patients. NKTR-255 is a polymer-conjugated IL-15 with extended half-life that can boost endogenous T and NK cells, as well as CD19 CAR-T activity in B cell malignancies. However, whether NKTR-255 is sufficient to overcome CAR-T dysfunction in the suppressive solid tumor microenvironment, and how NKTR-255 and CAR-Ts together re-shape endogenous anti-tumor immunity, is not known. Using an autochthonous mouse model of ROR1 + lung adenocarcinoma, we show that NKTR-255 significantly boosted accumulation, reduced exhaustion, and improved function of tumor-infiltrating CAR-T cells. Compared with NKTR-255 or CAR-T treatment alone, combination of NKTR-255 and CAR-T therapy synergistically increased tumor-infiltrating CD11b + cytotoxic NK cells, activated dendritic cells, and endogenous tumor-specific T cells that preserved a PD-1 + Tcf1 + stem-like phenotype. Consequently, NKTR-255 and CAR-T combination therapy induced complete elimination of ROR1 + tumor and significantly improved survival, with enhanced tumor control dependent on activity of both CAR-Ts and endogenous T cells. Altogether, our data suggest that combining NKTR-255 with CAR-T therapy is a promising strategy to enhance both CAR-T and endogenous anti-tumor immunity to promote coordinated control of aggressive tumors.

DOI: https://doi.org/10.64898/2025.12.11.693768
Nat Commun. 2025 Dec 30.

Intratumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ cDC1 infiltration and activates anti-tumor immunity.

Louise Gorline, Fillipe Luiz Rosa do Carmo, Pierre Bourdely, Jérémie Bornères, Nathan Vaudiau, Aurélie Semervil, Mathias Vetillard, Aboubacar Sidiki K Coulibaly, Natacha Jugniot, Agathe Ok, Mathilde Bausart, Oriane Fiquet, Marine Andrade, Dicken Fardol, Ikrame Haddar, Zeina Abou Nader, Judith Weber, Hannah Theobald, Matthieu Collin, Joseph Calmette, Giorgio Anselmi, Flavia Fico, Florent Ginhoux, Laleh Majlessi, Emmanuel L Gautier, Loredana Saveanu, Julie Helft, Marc Dalod, Mathilde Dusseaux, James P Di Santo, Stéphanie Hugues, Pierre Guermonprez.

Tumor infiltration by XCR1⁺ conventional dendritic cells (cDC1) correlates strongly with favorable prognosis and improved responses to immunotherapy. Yet, tumor-driven immunosuppressive programs restrict efficient cDC1 recruitment, highlighting the need for strategies to increase cDC1 access to the tumor microenvironment. Here, we establish a proof-of-concept cell-based immunotherapy that enhances the infiltration of circulating cDC1 progenitors and supports their local expansion. Intratumoral engraftment of autologous mesenchymal stromal cells engineered to express membrane bound FLT3L promotes cDC1 recruitment when combined with poly(I:C). We identify poly(I:C)-induced CXCL9 and CCL5 as essential chemokines controlling intratumoral cDC1 infiltration. Stromal cell-mediated local delivery of FLT3L together with CXCL9 and CCL5 is sufficient to enhance cDC1 infiltration in mice or humanized mice settings. Finally, this approach activates antitumor immunity and partially overcomes resistance to immune checkpoint blockade. Collectively, our data support the therapeutic potential of expanding intratumoral cDC1s through local and sustained delivery of FLT3L, CXCL9, and CCL5.

DOI: https://doi.org/10.1038/s41467-025-68018-3
Nat Immunol. 2025 Dec 29.

Tissue-resident exhausted and memory CD8+ T cells have distinct ontogeny, function and role in disease.

Simone L Park, Mark M Painter, Sasikanth Manne, Victor Alcalde, Maura McLaughlin, Matthew A Sullivan, Divij Mathew, Leonel Torres, Yinghui J Huang, David B Reeg, Naomi R Douek, Trenton Campos, Max Klapholz, Maria A Cardenas, Victoria Fang, Shin Foong Ngiow, Wumesh Kc, Rishi R Goel, Amy E Baxter, Jennifer E Wu, Melody Tan, Corbett T Berry, Christoph T Ellebrecht, Huang C Alexander, Emily Papazian, Ying Liu, Karthik Rajasekaran, Robert M Brody, Erica R Thaler, Devraj Basu, Ahmed Diab, Josephine R Giles, E John Wherry.

The presence of CD8+ T cells coexpressing residency and exhaustion molecules in chronic diseases often correlate with clinical outcomes; however, the relationship between these cells and conventional tissue-resident memory (TRM) cells or exhausted CD8+ T (TEX) cells is unclear. Here we show that chronic antigen stimulation drives development of tissue-resident TEX (TR-TEX) cells that are distinct from TRM cells generated after antigen clearance. TR-TEX and TRM cells are regulated by different transcriptional networks with only TR-TEX cells being Tox-dependent for residency programming. While TEX cells (including TR-TEX) are unable to generate TRM cells after antigen withdrawal, TRM cells differentiate into TEX cells upon chronic antigen exposure. Cell-state-specific transcriptional signatures reveal a selective association of TR-TEX cells with patient responses to immune checkpoint blockade, and only TR-TEX but not TRM cells responded to PD-1 pathway inhibition in vivo. These data suggest that TR-TEX and TRM cells are developmentally divergent cell states that share a tissue-residency program but have distinct roles in disease control.

DOI: https://doi.org/10.1038/s41590-025-02352-y
Discov Oncol. 2025 Dec 31.

Pan cohort immune biomarker of CD8 lymphocyte activation enabling HGSOC outcome prediction and treatment response.

Xinkui Liu, Zhen Zhang, Bin Wang, Liping Qin, Nannan Fan, Ruohan Wang, Xiaoyan Yu, Qiaoqiao Han, Zihan Lu, Siambi Kikete, Feifei Shi, Chu Chu, Yunhong Zhang, Liangzhong Niu, Ran Wei, Jiarui Wu, Xia Li.

   BACKGROUND: High-grade serous ovarian cancer (HGSOC) exhibits poor prognosis due to late diagnosis, chemoresistance, and limited responses to immune checkpoint inhibitors. Although tumor-infiltrating CD8+ T cells correlate with improved survival, current prognostic models remain inadequate. Thus, robust biomarkers linked to CD8+ T cell activation are urgently needed to guide clinical management.
METHODS: Transcriptomic and clinical profiles from 874 late-stage HGSOC patients were analyzed via single-sample gene set enrichment analysis for immune infiltration and weighted gene co-expression network analysis to identify CD8+ T cell-associated genes. An integrative machine learning approach was employed to develop a CD8⁺ T cell-associated immune prognostic signature (CIPS), which was then validated across multiple independent cohorts and benchmarked against 56 published models. CIPS was further characterized using single-cell RNA-seq analysis.
RESULTS: The resulting 10-gene signature independently predicted overall survival in all cohorts and consistently surpassed most clinicopathological variables and comparator models. Low-risk patients exhibited significantly enhanced CD8+ T cell and cytotoxic gene scores, correlating with better responses to chemotherapy and immunotherapy. CIPS inversely correlated with tumor-mutation burden, BRCA1/2 mutations and homologous-recombination deficiency. Single-cell analysis localized signature genes to T lymphocyte and myeloid compartments and linked elevated CIPS activity to augmented intercellular communication in platinum-resistant tumors.
CONCLUSION: CIPS captures a CD8+ T cell activation program that powerfully stratifies late-stage HGSOC, forecasts therapeutic benefit and offers a practicable biomarker for personalized immuno-oncology strategies.

Keywords:  CD8+ T cell; High-grade serous ovarian cancer; Machine learning; Tumor environment

DOI:  https://doi.org/10.1007/s12672-025-04363-5