bims-tuinly 2025-09-28 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–09–28
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Correlation study of tumor-infiltrating lymphocytes combined with residual cancer burden and prognosis in breast cancer patients receiving neoadjuvant chemotherapy.
Advances in Adoptive Cell Therapies in Cancer: From Mechanistic Breakthroughs to Clinical Frontiers and Overcoming Barriers.
Efficient expansion of tumor-infiltrating lymphocytes from gynecologic cancer.
The opportunities and barriers for developing tumour-infiltrating lymphocyte therapy for patients with advanced genitourinary cancers.
Tumor-Stroma Ratio, Infiltrating Lymphocytes, and Their Combined Profiles in Oral Cancer Prognosis.
Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.
AI-informed computational pathology classifier predicts outcomes across treatment modalities in muscle-invasive urothelial carcinoma.
Case Report: A Multi-Peptide Vaccine Targeting Individual Somatic Mutations Induces Tumor Infiltration of Neoantigen-Specific T Cells in a Patient with Metastatic Colorectal Cancer.
Efficacy and safety of nivolumab monotherapy in patients with high PD-1 positive CD8/Treg ratio in advanced NSCLC and GC: A phase II, multicenter study.
CD103+CD8+ tissue-resident memory T lymphocytes of melanoma boost anti-tumour immunity and predict immunotherapy outcomes.
Prediction of neoadjuvant therapy response in breast cancer based on interpretable artificial intelligence.
Harnessing the Inflammatory Signature: A Review for Biomarkers in Inflammatory Breast Cancer.
Evaluating the significance of combining PD-L1 and TILs as biomarkers in non-small cell lung cancer patients treated with immunotherapy: a systematic review.
M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling.
CD7 regulates the persistence of terminally exhausted CD8+ T cells during chronic infection.
FLT3L combined with GM-CSF induced dendritic cells drive broad tumor-specific CD8+ T cell responses and remodel the tumor microenvironment to enhance anti-tumor efficacy.
Tumor-targeted delivery of CXCL10 by mesenchymal stromal cells potentiates adoptive T cell therapy to treat solid tumors.
A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy.
Transcriptome Analysis Unravels CD4+ T-Cell and Treg-Cell Differentiation in Ovarian Cancer.

Front Oncol. 2025 ;15 1538326

Correlation study of tumor-infiltrating lymphocytes combined with residual cancer burden and prognosis in breast cancer patients receiving neoadjuvant chemotherapy.

Zexin Hou, Xueyuan An, Guangmin Meng, Hongmei Zhao, Shanghua Liao, Xiaomin Long, Lingjun Zou, Wen Wu, Li Feng, Guanghui Liao.

   Purpose: This study investigates the feasibility of utilizing a combination of tumor-infiltrating lymphocytes (TILs) and residual cancer burden (RCB) to predict the prognosis of breast cancer (BC) individuals post-neoadjuvant chemotherapy (NAC).
Methods: Patients with BC who underwent surgery following NAC were recruited from three medical centers for this research. RCB and TIL levels were determined using established guidelines, and the integration of RCB and TIL assessments was termed "RCB-TILs". The relationship between RCB-TILs and patients' clinicopathological variables was analyzed, alongside the link between RCB-TILs and disease-free survival (DFS).
Results: The study comprised 242 BC patients who underwent NAC, among whom 98 were identified as RCB-TILs (+), while 144 were classified as RCB-TILs (-). Multivariate analysis demonstrated that RCB-TILs (+) served as an independent factor impacting recurrence following NAC across all BC patients (hazard ratio [HR] = 0.225, 95% confidence interval [CI]: 0.099 - 0.508, P < 0.001), including hormone receptor-positive patients (HR = 0.213, 95%CI: 0.067 - 0.682, P = 0.009), HER2-positive patients (HR = 0.216, 95%CI: 0.048 - 0.968, P = 0.045), and those with triple-negative BC (HR = 0.220, 95%CI: 0.049 - 0.989, P = 0.048).
Conclusions: RCB-TILs (+) are correlated with extended DFS in BC patients who have undergone surgery post-NAC. In these individuals, RCB-TILs may provide a more sensitive predictor of DFS than RCB or TILs individually.

Keywords:  breast cancer; disease-free survival; neoadjuvant chemotherapy; residual cancer burden; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3389/fonc.2025.1538326
Med Sci (Basel). 2025 Sep 15. pii: 190. [Epub ahead of print]13(3):

Advances in Adoptive Cell Therapies in Cancer: From Mechanistic Breakthroughs to Clinical Frontiers and Overcoming Barriers.

Syed Arman Rabbani, Mohamed El-Tanani, Yahia El-Tanani, Rakesh Kumar, Shrestha Sharma, Mohammad Ahmed Khan, Suhel Parvez, Alaa A A Aljabali, Mohammad I Matalka, Manfredi Rizzo.

  Adoptive cell therapies (ACTs) have revolutionized cancer treatment by harnessing the specificity and potency of T lymphocytes. Chimeric antigen receptor (CAR)-T cells have achieved landmark successes in B-cell malignancies and multiple myeloma. Tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells offer complementary strategies to target solid tumors and intracellular antigens. Despite these advances, ACTs face challenges including cytokine release syndrome, neurotoxicity, on-target/off-tumor effects, manufacturing scalability, and immunosuppressive tumor microenvironments. Innovative strategies, such as dual-antigen targeting, localized delivery, checkpoint blockade combinations, gene-editing, and machine-learning-guided antigen discovery, are being used to mitigate toxicity, enhance efficacy, and streamline production. As CAR-T, TIL, and TCR modalities converge with advances in manufacturing and computational biology, the next generation of "living drugs" promises broader applicability across hematologic and solid tumors, improved safety profiles, and better treatment outcomes for patients. This review details the evolution of ACTs from first-generation CAR constructs to next-generation "armored" designs. It also focuses on the development and clinical deployment of TIL and TCR therapies. Furthermore, it synthesizes mechanisms, pivotal clinical trial outcomes, and ongoing challenges of ACTs. It also highlights strategies that will drive broader, safer, and more durable applications of these therapies across hematologic and solid tumors.

Keywords:  CAR; T cell; adoptive cell therapy; immunotherapy; multiple myeloma; solid tumors; tumor infiltrating lymphocytes

DOI:  https://doi.org/10.3390/medsci13030190
J Immunol. 2025 Sep 26. pii: vkaf259. [Epub ahead of print]

Efficient expansion of tumor-infiltrating lymphocytes from gynecologic cancer.

Tetsuya Matsukawa, Tsunenori Ouchida, Taeko Hayakawa, Toshiaki Yoshikawa, Yusuke Ito, Hitomi Kasuya, Chisato Umehara, Satoshi Inoue, Tatsuyuki Chiyoda, Hiroshi Nishio, Wataru Yamagami, Waki Hosoda, Shiro Suzuki, Yuki Kagoya.

  Tumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive immunotherapy potentially applicable to many types of solid tumors. Although gynecologic malignancies are promising targets for TIL therapy, its objective efficacy has not been established. Current TIL culture typically involves incubation of dissociated samples with high-dose IL-2 (HD-IL2) for weeks to enrich tumor-reactive T cells. While this protocol has been successfully used for melanoma TIL, it has not necessarily been optimized for other cancers. Here we investigated the method of efficiently expanding TILs derived from patients with gynecological cancers. TILs were incubated with HD-IL2 (HD-IL2-TILs) or stimulated with K562 cells expressing anti-CD3 mAb and CD80 (αCD3/CD80-TILs). We found that the αCD3/CD80-TILs showed significantly better proliferation than HD-IL2-TILs. The TIL populations that predominantly expanded upon αCD3/CD80 stimulation expressed high levels of PD-1 and CD28. CD28 co-stimulation was essential to overcome PD-1-mediated signals for growth suppression. We also identified DUSP4 as a negative regulator of TIL proliferation by downregulating ERK phosphorylation. The αCD3/CD80-TILs were reactive to tumor cells as shown by IFN-γ secretion and CD107a expression. Moreover, the αCD3/CD80-TILs were efficiently transduced with a chimeric cytokine receptor that we had previously developed to provide constitutive IL-7 signaling, resulting in superior in vivo persistence and antitumor effects without exogenous cytokine support in mouse models. Collectively, this study shows that direct stimulation of TILs with anti-CD3 mAb and CD28 co-stimulation achieves efficient expansion of tumor-reactive TILs. Genetic engineering of cytokine signaling in TILs may further enhance TIL functions and replace cytokine administration after TIL infusion.

Keywords:  CD28; TIL; adoptive immunotherapy; cytokine; gynecologic cancers

DOI:  https://doi.org/10.1093/jimmun/vkaf259
Nat Rev Urol. 2025 Sep 26.

The opportunities and barriers for developing tumour-infiltrating lymphocyte therapy for patients with advanced genitourinary cancers.

Marine Potez, Gabriel Roman Souza, Philippe E Spiess, Shari Pilon-Thomas, Jad Chahoud.

Adoptive cell therapy using tumour-infiltrating lymphocytes (TILs) has been a very successful model of enhancing immune-based therapies. Clinical benefits have been shown for patients with advanced melanoma, leading to the first FDA approval for this immune modality in 2024. Although clinical trials conducted decades ago for advanced renal-cell cancer did not show significant clinical benefits, recent advances in the TIL generation process, manipulation techniques, preparative regimens and combination with immune checkpoint inhibitors offer new hope for reexploring optimized TIL therapy for genitourinary cancers. The current landscape of TIL therapy has seen progress in TIL manufacturing, optimization and delivery methodologies that have the potential to improve the safety and efficacy of TIL therapy in the management of advanced genitourinary malignancies. Furthermore, innovative combination approaches and novel strategies could enhance the clinical viability of TIL therapy and warrant evaluation in clinical trials treating patients with genitourinary cancers.

DOI: https://doi.org/10.1038/s41585-025-01088-6
Oral Dis. 2025 Sep 22.

Tumor-Stroma Ratio, Infiltrating Lymphocytes, and Their Combined Profiles in Oral Cancer Prognosis.

Michal Herman, Katerina Kopecka, Jaroslav Michalek, Richard Pink, Jana Zapletalova, Sylva Hotarkova, Michal Hendrych, Michal Mozola, Marketa Hermanova.

   BACKGROUND: Tumor microenvironment and immune response-related histopathological features were identified as potential biomarkers in many tumor types, including oral squamous cell carcinoma (OSCC). We assessed the prognostic significance and correlations of tumor-stroma ratio (TSR), tumor-infiltrating lymphocytes (TILs), and their combined profiles in OSCC.
METHODS: The study included 114 patients with resected OSCC. Stromal TILs and TSR were evaluated on the hematoxylin and eosin-stained tissue sections according to International Immuno-Oncology Biomarker Working Group criteria and recommendations for the assessment of TSR and categorized (into stroma-high and stroma-low; TILs high and TILs low). Clinicopathological correlations and survival analyses were performed.
RESULTS: Correlations of TSR and TILs with clinicopathological parameters, including grade, stage, perineural invasion, and lymph node metastasis, were found. TSR (stroma-high) was independently associated with shortened disease-specific, disease-free, and overall survival. Low TILs were associated with worse survival rates; these associations were not significant in multivariate analysis. However, the combined profiles of TILs with TSR showed a gradually increased risk of recurrence or death, from stroma-low/TILs high to stroma-high/TILs low tumors.
CONCLUSION: The findings support that the evaluation of TSR, TILs, and their combinations provides significant information on OSCC hazard discrimination and prognostication, suggesting their potential implementation in routine pathological reports.

Keywords:  histopathology; oral squamous cell carcinoma; prognosis; tumor‐infiltrating lymphocytes; tumor‐stroma ratio

DOI:  https://doi.org/10.1111/odi.70101
Immunity. 2025 Sep 25. pii: S1074-7613(25)00414-5. [Epub ahead of print]

Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4.

Coral Del Mar Alicea Pauneto, Brian P Riesenberg, Evelyn J Gandy, Andrew S Kennedy, Genevieve T Clutton, Jessica W Hem, Katie E Hurst, Elizabeth G Hunt, Jarred M Green, Brian C Miller, Steven P Angus, Gary L Johnson, Robert J Esther, Jennifer L Guerriero, Peng Gao, David R Soto-Pantoja, Robert L Ferris, Jennifer L Modliszewski, Michael F Coleman, H Kay Chung, J Justin Milner, Stergios J Moschos, R Luke Wiseman, Jessica E Thaxton.

  Metabolic stress in the tumor microenvironment (TME) promotes T cell dysfunction and immune checkpoint inhibitor (ICI) resistance. We examined the contribution of activating transcription factor 4 (ATF4), the central node of the integrated stress response (ISR), to T cell dysfunction in tumors. CD8+ tumor-infiltrating lymphocytes (TILs) in patient samples exhibited chronic ATF4 activity, which was reflected across various tumor models. Hypoxia in the TME imposed chronic ATF4 activity via the ISR kinases. ATF4 overexpression in CD8+ T cells induced metabolic polarity, mitochondrial oxidative stress, and cell death, impairing antitumor immunity. Chronic ATF4 transcriptional activity replicated the terminal exhaustion CD8+ T cell state independent of T cell receptor (TCR) stimulation. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted CD8+ TIL viability, enabling response to programmed cell death protein-1 (PD-1) inhibitor therapy and conferring protection from re-emergent disease. Thus, the ISR converges on chronic ATF4 activity in CD8+ TILs as a barrier to ICI response, positioning ISR therapeutics as candidates for immunotherapy.

Keywords:  ATF4; T cell; hypoxia; immunotherapy; integrated stress response; metabolism; mitochondria; tumor microenvironment

DOI:  https://doi.org/10.1016/j.immuni.2025.09.003
Cancer Lett. 2025 Sep 23. pii: S0304-3835(25)00631-7. [Epub ahead of print]634 218059

AI-informed computational pathology classifier predicts outcomes across treatment modalities in muscle-invasive urothelial carcinoma.

Kamal Hammouda, Naoto Tokuyama, Germán Corredor, Tilak Pathak, Rishi Dakarapu, Elizabeth Genega, Omar Y Mian, Paul G Pavicic, C Marcela Diaz-Montero, Tuomas Mirtti, Xavier Farré, Shilpa Gupta, Anant Madabhushi.

  Urothelial carcinoma (UC) is one of the leading causes of cancer-related mortality, and effective, scalable biomarkers for treatment planning remain limited. We present UC-TIL, an artificial intelligence (AI)-based model that quantifies spatial patterns of tumor-infiltrating lymphocytes (TILs) from routine H&E-stained slides to predict survival and immunotherapy response. We analyzed 558 whole-slide images across three cohorts: TCGA (D0&1, N = 292), Emory (D2, N = 161), and TRRC2819 (D3, N = 105), spanning chemotherapy and immune checkpoint inhibitor (ICI) treatments. UC-TIL classification was associated with OS (HR = 2.11, 95 %CI:1.01-4.41, p = 0.011) and PFS (HR = 3.68, 95 %CI:1.07-12.65, p = 0.0012) in locally advanced disease (D1 and D2), with consistent results in metastatic disease (D3) (HR = 1.73, 95 %CI:1.08-2.77, p = 0.043; PFS HR = 1.73, 95 %CI:1.07-2.81, p = 0.047). In the ICI-treated D3 cohort, UC-TIL achieved AUC = 0.757 and identified non-responders with 91 % specificity. UC-TIL enables reliable risk stratification and treatment response prediction in both locally advanced and metastatic urothelial carcinoma by analyzing spatial TIL patterns from standard pathology slides. These findings position UC-TIL as a readily deployable tool to guide personalized therapy across multiple clinical settings.

Keywords:  Artificial intelligence; Digital pathology; Metastatic urothelial carcinoma; Muscle-invasive bladder cancer; Predictive biomarker; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.canlet.2025.218059
Vaccines (Basel). 2025 Sep 11. pii: 960. [Epub ahead of print]13(9):

Case Report: A Multi-Peptide Vaccine Targeting Individual Somatic Mutations Induces Tumor Infiltration of Neoantigen-Specific T Cells in a Patient with Metastatic Colorectal Cancer.

Armin Rabsteyn, Henning Zelba, Borong Shao, Lisa Oenning, Christina Kyzirakos, Simone Kayser, Tabea Riedlinger, Johannes Harter, Magdalena Feldhahn, Dirk Hadaschik, Florian Battke, Veit Scheble, Alfred Königsrainer, Saskia Biskup.

   BACKGROUND/OBJECTIVES: Fully personalized peptide vaccines targeting tumor-specific mutations are a promising treatment option for patients in an adjuvant but also advanced/metastatic disease situation in addition to non-personalized standard therapies. Here, we report a patient's case with advanced metastatic colorectal cancer (mCRC) who was treated with a neoantigen-derived multi-peptide vaccine in addition to standard of care.
METHODS: Tumor-specific mutations were identified by whole exome and transcriptome sequencing. An individualized peptide vaccine was designed using an in-house developed epitope prediction and vaccine design platform. In this case, the vaccine consisted of 20 peptides targeting 18 distinct mutations. The vaccine was administered according to a prime-boost scheme for a total of 12 vaccinations. Vaccine immunogenicity was determined by stimulation of patient T cells with vaccinated peptides and subsequent intracellular cytokine staining (ICS). Tumor-infiltrating lymphocytes (TIL) were analyzed by ICS and T cell receptor beta chain (TCRβ) sequencing.
RESULTS: The patient survived for 41 months since initial diagnosis despite continuous disease progression under all therapeutic interventions. The vaccination induced multiple neoantigen-specific T cell responses in the patient without notable side effects. Two liver metastases were resected five months after the start of vaccination, and TIL were extracted and cultured. Analysis of TIL cultures revealed tumor infiltration by vaccine-induced neoantigen-specific T cells in only one of the metastases. TCRβ sequencing of neoantigen-specific T cells and tumor tissues supported this finding. Vaccine-targeted variants were reduced or absent in the metastasis with vaccine-specific T cell infiltration.
CONCLUSIONS: This case demonstrates immunogenicity of a neoantigen-derived peptide vaccine and highlights tumor-infiltrating capabilities and potential cytotoxicity of vaccine-induced T cells in mCRC.

Keywords:  TCRβ sequencing; metastatic colorectal cancer; neoantigens; personalized peptide vaccination; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/vaccines13090960
Cancer Res Commun. 2025 Sep 25.

Efficacy and safety of nivolumab monotherapy in patients with high PD-1 positive CD8/Treg ratio in advanced NSCLC and GC: A phase II, multicenter study.

Kohei Shitara, Motohiro Tamiya, Kyoichi Okishio, Hisashi Hosaka, Katsunori Shinozaki, Nobuhiko Seki, Hiroki Hara, Yukiya Narita, Takeshi Shiraishi, Yosuke Tamura, Akihito Tsuji, Kunihiro Tsuji, Naohiro Watanabe, Hiroshi Tanaka, Toshifumi Yamaguchi, Kensei Yamaguchi, Hiroki Izumi, Yasunori Ushida, Hideaki Suna.

Background It is challenging to identify the appropriate patients who benefit from anti-PD-1/PD-L1 monotherapy. For predicting effectiveness of anti-PD-1/PD-L1 monotherapy, this open-label phase Ⅱ study (ONO-4538-88) evaluated the potential of the tumor infiltrating lymphocytes (TIL) biomarker: the balance between cytotoxic T cells and regulatory T cells. Methods Patients with advanced non-small cell lung cancer (NSCLC) or gastric cancer (GC) were screened between March 2021 and January 2022. Eligible patients who met the prespecified TIL biomarker criteria received nivolumab monotherapy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS) and progression-free survival (PFS). Conventional biomarkers (tumor proportion score, combined positive score, tumor mutation burden, and microsatellite instability) were exploratorily analyzed, and safety was also assessed. Results Thirty-seven patients with NSCLC and 127 patients with GC were eligible for TIL analysis: 6 (16.2%) and 15 patients (11.8%) met the TIL biomarker criteria, respectively; a part of them were assessed. For NSCLC and GC, the ORR was 80.0% (4/5 patients) and 36.4% (4/11 patients), respectively; all the 5 patients and 5/11 patients had a reduction in tumor size, respectively; the median OS was not reached and 25.00 months, respectively; and the median PFS was not reached and 5.59 months, respectively. Treatment-related adverse events (TRAEs) occurred in 13/19 patients overall: 5/6 patients for NSCLC and 8/13 patients for GC. Conclusions Although the low positive rate of the TIL biomarker limits interpretation, the promising ORRs suggest the signs of the TIL biomarker's predictability for the nivolumab monotherapy.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0169
Clin Transl Med. 2025 Sep;15(9): e70464

CD103+CD8+ tissue-resident memory T lymphocytes of melanoma boost anti-tumour immunity and predict immunotherapy outcomes.

Tianyi Zhang, Junquan Song, Yinlam Li, Kangjie Shen, Jiangying Xuan, Yuan Gao, Lili Lu, Zhi Pang, Lu Wang, Yang Yang, Zixu Gao, Qianrong Hu, Yu Zhu, Chenlu Wei, Shaoluan Zheng, Rongkui Luo, Yingyong Hou, Yuhong Zhou, Chuanyuan Wei, Jianying Gu.

   BACKGROUND: Immunotherapy has revolutionised melanoma treatment, providing significant clinical benefits by reactivating the anti-tumour immune system. CD8+ tissue-resident memory T lymphocytes (CD8+ TRM) have emerged as crucial mediators of anti-tumour immunity, while their specific role in melanoma remains poorly understood.
METHODS: Following CD8+CD45.1+ OT-1 cell adoptive transfer into CD45.2+ mice, we employed magnetic separation to purify and analyse resident memory CD8+ T cells (TRM). We use multiple immunohistochemistry (mIHC) to evaluate the spatial distribution of CD8+ TRM in ZS melanoma cohort. Additionally, the biological function of CD8+ TRM and their impact on anti-tumour immunity are explored using scRNA sequencing and spatial transcriptomics, coupled with in vivo/in vitro experiments. Finally, CD8+ TRM utility as an immunotherapy response predictor is examined across several independent cohorts.
RESULTS: CD8+ TRM demonstrates potent tumour-killing capabilities in melanoma, with CD103 as a distinctive marker. High CD103+CD8+ TRM infiltration in tumour tissues strongly correlates with improved prognosis in melanoma patients. In vivo adoptive transfer of CD103+CD8+ TRM effectively inhibits melanoma progression. Mechanistically, CD103 activates the integrin-dependent PI3K/AKT signalling cascade, promoting both proliferation and anti-tumour effector functions of CD8+ TRM. Notably, CD103+CD8+ TRM preferentially localises within tertiary lymphoid structures (TLS), and its adoptive transfer promotes TLS formation. Clinically, CD103+CD8+ TRM is enriched in immunotherapy-responsive patients and serves as a strong predictor for immune checkpoint blockade (ICB) treatment outcomes.
CONCLUSIONS: CD103+ CD8+ TRM cells in melanoma play a key role in the anti-tumour immune process and can also be used as a reliable predictor of immunotherapy efficacy.
KEY POINTS: CD103 is a reliable marker of tissue-resident memory (TRM) CD8+ T cells in melanoma. CD103+CD8+ TRM cells exhibit potent anti-tumour immune activity. CD103+CD8+ TRM cells predict favourable responses to immunotherapy in melanoma.

Keywords:  TIL; immunotherapy; melanoma; tissue‐resident memory T lymphocytes

DOI:  https://doi.org/10.1002/ctm2.70464
Int J Surg. 2025 Sep 24.

Prediction of neoadjuvant therapy response in breast cancer based on interpretable artificial intelligence.

Yao Zhou, Xin Shu, Fan Wang, Hui Xu, Hong-Qun Tang, Hao Fang, Jing Huang, Yi-Wei Wang, Hong-Liang Ji, Shi-Wei Zhang, Wei Qu, Jian-Hong Tu, Fan Niu, Li-Bin Deng.

   BACKGROUND: To develop an AI-based predictive model for neoadjuvant therapy (NAT) efficacy in breast cancer, we integrated multimodal data and analyzed tumor microenvironment (TME) features to provide interpretability.
METHODS: We retrospectively analyzed H&E-stained whole-slide images (WSIs) from a multi-center cohort of breast cancer patients receiving NAT to develop an AI predictive model. The cohort was stratified into training, test, internal validation, and external validation sets. Feature extraction used UNI and classification employed a multiple instance learning (MIL) framework. Model performance was evaluated via ROC curve analysis (AUC, precision, specificity, recall). Molecular mechanisms underlying model predictions were explored using TCGA multimodal data, integrating differential gene expression profiling with pathway enrichment analysis (GO, KEGG). TME component correlations with model scores were also investigated.
RESULTS: The AI model demonstrated robust discriminative capacity across three residual cancer burden (RCB)-based classification tasks in 826 patients from two centers, achieving peak performance in subtask 2 (NAT-sensitive: RCB 0-1 vs. NAT-resistant: RCB 2-3). For subtask 2, AUCs were 0.901 (training), 0.858 (test), 0.808 (internal validation), and 0.819 (external validation). Molecular analysis linked the model's predictive efficacy to tumor cell cycle processes. TME analysis revealed positive correlations between model scores and activated immune cells (M0/M1 macrophages, dendritic cells), and negative correlations with inhibitory cells (M2 macrophages, resting mast cells). Crucially, the model's predictive scores were closely related to tumor-infiltrating lymphocytes (TILs), with spatial colocalization observed between classification weights and TILs distribution. Significant differences in TILs levels occurred across model score strata, validating the model's biological plausibility in predicting NAT response mechanisms.
CONCLUSION: We developed an interpretable AI model that predicts response to neoadjuvant therapy in breast cancer using H&E slides. The model's predictions are biologically interpretable, correlating with TME dynamics and spatial TIL patterns, offering a novel strategy for personalizing NAT treatment strategies.

Keywords:  breast cancer; evaluation of therapeutic effect; explainable artificial intelligence; neoadjuvant therapy; tumor microenvironment

DOI:  https://doi.org/10.1097/JS9.0000000000003326
QJM. 2025 Sep 24. pii: hcaf219. [Epub ahead of print]

Harnessing the Inflammatory Signature: A Review for Biomarkers in Inflammatory Breast Cancer.

Yingjia Hu, Jian Li, Xinyi Wang, Hongfei Ji, Xingjian Niu.

Inflammatory breast cancer (IBC) is a highly aggressive breast cancer subtype characterized by rapid progression and poor survival outcomes. In recent years, research on the clinical and molecular features of IBC has brought new hope for its diagnosis and treatment. However, the prognosis of IBC remains extremely poor and novel biomarkers to identify the individual characteristics of patients with IBC are warranted. This review discussed the latest research on IBC biomarkers, especially the unique clinical IBC characterization-related biomarkers, including tumor emboli-related markers and tumor microenvironment (TME)-related markers. Biomarkers based on immune cells in the TME, such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), mast cells, cytokines, and chemokines (e.g., CCL2), may be involved in the development, progression, and treatment resistance of IBC. This study also identified effective biomarkers for IBC and emphasized unique clinical IBC characterization-related biomarkers that may provide strong evidence in IBC diagnosis, prognosis, and therapeutics.

DOI: https://doi.org/10.1093/qjmed/hcaf219
BJC Rep. 2025 Sep 22. 3(1): 65

Evaluating the significance of combining PD-L1 and TILs as biomarkers in non-small cell lung cancer patients treated with immunotherapy: a systematic review.

Y Derraze, S M S Hashemi, E B Ulas, K A Ziesemer, B Lissenberg-Witte, T Radonic, I Bahce.

In advanced non-small cell lung cancer (NSCLC), programmed death-ligand 1 (PD-L1) expression is a well-established but suboptimal biomarker for predicting response to immune checkpoint inhibitors (ICIs). Tumor-infiltrating lymphocytes (TILs), particularly CD8+ subsets, have demonstrated potential as complementary biomarker. Despite existing data on each biomarker individually, the combined effect is not fully understood. A systematic search of Ovid/Medline, Embase, and Web of Science identified studies on CD8+ TILs and PD-L1 in NSCLC patients treated with ICIs. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR) and durable clinical benefit (DCB). Study quality was assessed using the Newcastle-Ottawa Scale. Thirteen studies (2490 patients) were included. PD-L1 expression was associated with longer PFS in 6 of 8 studies (HR: 0.67, 95% CI: 0.49-0.90) but did not significantly correlate with OS. TILs alone showed no significant predictive value for PFS or OS. However, combining both biomarkers provided the strongest predictive value for PFS (HR: 0.39, 95% CI: 0.27-0.57) and OS (HR: 0.42, 95% CI: 0.31-0.56). Combining PD-L1 and TILs may more effectively predict PFS and OS than either biomarker alone, though their clinical application remains complex.

DOI: https://doi.org/10.1038/s44276-025-00174-x
Biochim Biophys Acta Mol Basis Dis. 2025 Sep 18. pii: S0925-4439(25)00404-1. [Epub ahead of print] 168056

M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling.

Yining Feng, Fei Chen, Chenglong Mu, Luqi Wang, Yuhan Jiang, Dan Liu, Dameng Li, Chen Liang, Yanhua Zhai, Tao Yang, Alan Wells, Amanda M Clark, Liang Wei, Bo Ma.

  Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, playing a key role in breast cancer progression and chemotherapy response. While TAMs exhibit diverse phenotypes, the M1/M2 classification remains widely used. M1-like macrophages are known for tumor-killing properties, whereas M2-like macrophages promote tumor growth. However, the impact of TAM subtypes on chemotherapy response remains inconsistent. In this study, we found that M1-like macrophages or their conditioned medium (CM) induced greater breast cancer (BrCa) cell death and inhibited proliferation compared to M2-like macrophages. Surprisingly, BrCa cells surviving M1-like macrophage-induced killing displayed increased chemotherapy resistance, independent of proliferation. RNA sequencing also revealed upregulation of the JAK-STAT pathway and elevated phosphorylated STAT3 in these cancer cells. Inhibition of JAKs with Ruxolitinib reduced STAT3 activation and restored chemotherapy sensitivity. Our findings highlight the dual role of M1-like macrophages, demonstrating both tumoricidal activity and the potential to induce chemotherapy resistance in surviving tumor cells, offering insights for macrophage-targeted therapies.

Keywords:  Breast cancer; Chemoresistance; M1-like macrophages; M2-like macrophages

DOI:  https://doi.org/10.1016/j.bbadis.2025.168056
Cell Rep. 2025 Sep 18. pii: S2211-1247(25)01087-3. [Epub ahead of print]44(10): 116316

CD7 regulates the persistence of terminally exhausted CD8+ T cells during chronic infection.

Sean Hyslop, Colby J Hofferek, Maria V Stegantseva, Emerald Kan, Kelli A McCord, Victor M Alvarez, Amanda Y Xia, Jacob P Conarty, Andreas Wieland, William H Hudson.

  CD8+ T cell exhaustion limits immune responses during cancer and chronic infection. We identify CD7 as a tissue-specific regulator of terminally exhausted CD8+ T cells during chronic infection. CD7 expression progressively increases during exhaustion, reaching its highest levels on a subset of CD101+Tim3low terminally exhausted cells that arise in the liver. Transcriptomic analysis revealed that CD7-deficient terminally exhausted cells display altered expression of co-stimulatory, translational, and effector genes, correlating with markedly reduced persistence and increased apoptotic susceptibility. Importantly, CD7 is preferentially upregulated on PD-1+CD39+ tumor-infiltrating lymphocytes in human head and neck squamous cell carcinoma, suggesting that CD7 may play a conserved role in promoting exhausted T cell survival. These findings reveal a function for CD7 in sustaining terminally exhausted CD8+ T cells and demonstrate that CD7 signaling is a critical regulator of T cell persistence during chronic infection.

Keywords:  CD7; CD8 T cell; CP: Immunology; LCMV; T cell; T cell exhaustion; immunology; scRNA-seq; viral immunology

DOI:  https://doi.org/10.1016/j.celrep.2025.116316
Front Immunol. 2025 ;16 1649891

FLT3L combined with GM-CSF induced dendritic cells drive broad tumor-specific CD8+ T cell responses and remodel the tumor microenvironment to enhance anti-tumor efficacy.

Qian Zheng, Jiajie Zhang, He Sui, Yu Sun, Ningning Lv, Lin Liu, Ming Qu, Jiateng Tan, Bin Zhang, Zhanhao Mo.

   Background: Dendritic cells (DCs) play a crucial role in anti-tumor immunity by capturing, processing, and presenting tumor antigens to T cells, making DC-based immunotherapy a promising approach for cancer treatment. However, the most commonly used clinical strategy still relies on inducing DCs in vitro using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL - 4) (GM/IL4-DCs), which often results in a heterogeneous cell population with suboptimal anti-tumor function. Here, we compared DCs generated by co-stimulating with FMS-like tyrosine kinase 3 ligand (FLT3L) and GM-CSF (FL/GM-DCs) with the conventional GM/IL4-DCs.
Method: To compare the functional differences of DCs induced by different methods, we conducted a comprehensive study. Mouse bone marrow cells were continuously cultured for 9 days in a FLT3L/GM-CSF-containing medium. After cell collection, we analyzed the composition, subpopulations, and status of FL/GM-DCs using flow cytometry and scRNA-seq. Flow cytometry was also used to assess their antigen presentation and ability to stimulate T cells. In vivo experiments were performed to examine their distribution, anti-tumor effects, and therapeutic responses in tumor models. Finally, combining scRNA-seq and scTCR-seq, we explored the mechanisms by which FL/GM-DCs reshape the tumor microenvironment.
Results: The results showed that FL/GM-DCs exhibited a unique subpopulation distribution, characterized by an abundance of conventional cDC subpopulations, and demonstrated enhanced cross-antigen presentation capabilities. Notably, FL/GM-DCs were able to induce a broader and more tumor-specific CD8+ T cell response, effectively reshaping the tumor microenvironment by promoting the infiltration of cytotoxic T lymphocytes (CTLs) and reducing immunosuppressive components. In contrast, GM/IL4-DCs contained fewer cDC subpopulations, eliciting a weaker initial CD8+ T cell response and yielding relatively inferior anti-tumor effects.
Conclusion: In summary, FLT3L combined with GM-CSF induced DCs, through their unique subpopulation composition and functional state, can more effectively expand tumor-specific CD8+ T cells and reshape the tumor microenvironment, thereby achieving superior immunotherapy outcomes. This study highlights the potential of FL/GM-DCs as a next-generation DC platform, paving the way for improved clinical translation of DC-based adoptive cancer immunotherapies.

Keywords:  DCs; FLT3L; GM-CSF; anti-tumor efficacy; cDC1; dendritic cells

DOI:  https://doi.org/10.3389/fimmu.2025.1649891
Biomed Pharmacother. 2025 Sep 20. pii: S0753-3322(25)00773-5. [Epub ahead of print]192 118579

Tumor-targeted delivery of CXCL10 by mesenchymal stromal cells potentiates adoptive T cell therapy to treat solid tumors.

Jeong Ho Yoon, Gyu-Bum Yeon, Hojae Lee, Hyunseo An, Jiwon Oh, Seok-Jin Kang, In-Byung Park, Seon Ah Lim, Soo Seok Hwang, Dae-Sung Kim, Ji Hyung Kim, Taehoon Chun, Yang-Xin Fu, Joonbeom Bae.

  Limited T cell infiltration into solid tumors remains one of the major obstacles to successful cancer immunotherapy, particularly for adoptive cell therapy (ACT). Although the chemokine CXCL10 recruits T cells, its direct therapeutic application is hampered by poor pharmacokinetics, systemic leakage, and failure to establish stable concentration gradients required for effective cell migration. To overcome these challenges, we engineered mesenchymal stromal cells (MSCs) to co-express NAD(P)H quinone oxidoreductase 1 (NQO1) for enhanced survival and CXCL10-Fc fusion protein for sustained chemokine delivery (NIP-MSCs). The engineered MSCs exhibited resilience to tumor microenvironment conditions through improved redox homeostasis, resulting in enhanced persistence and sustained IP10-Fc production in vivo. Crucially, tumor-targeted delivery of CXCL10-Fc established potent chemotactic gradients with minimal systemic leakage, dramatically increasing both endogenous and adoptively transferred T cell recruitment to tumor site. In syngeneic mouse models, NIP-MSC treatment significantly suppressed tumor growth through enhanced CD8+ T cell infiltration. When combined with ACT in melanoma models, NIP-MSCs resulted in superior tumor control and significantly prolonged survival compared to conventional approaches. This work validates NIP-MSCs as a promising platform to overcome T cell exclusion and potentiate immunotherapy efficacy in solid tumors.

Keywords:  Adoptive T cell therapy (ACT); CXCL10; Cancer immunotherapy; Cell therapy; Chemotaxis; Mesenchymal stromal cell (MSCs)

DOI:  https://doi.org/10.1016/j.biopha.2025.118579
Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2516951122

A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy.

Yapeng Su, Ashley Thelen, Lena V Wirth, Cody M Jenkins, Sam R Mak, Daniel G Chen, Raphael Gottardo, Philip D Greenberg.

  Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8+ T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β-mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.

Keywords:  T cell engineering; T cell receptor (TCR) T cell therapy; adoptive T cell therapy; cancer immunotherapy

DOI:  https://doi.org/10.1073/pnas.2516951122
Biomolecules. 2025 Aug 27. pii: 1241. [Epub ahead of print]15(9):

Transcriptome Analysis Unravels CD4+ T-Cell and Treg-Cell Differentiation in Ovarian Cancer.

Baoyi Shao, Bo Sun, Zhongdang Xiao.

   BACKGROUND: Ovarian cancer ranks as the fifth leading cause of cancer-related mortality among women worldwide. Owing to its insidious onset and lack of early symptoms, over 70% of patients are diagnosed at advanced stages.
METHODS: This study provides a comprehensive transcriptomic analysis of tumor-infiltrating CD4+ T cells in ovarian cancer, highlighting regulatory T cells (Tregs) as the dominant subset. By integrating seven multicenter ovarian cancer single-cell RNA-seq datasets, a robust metadata resource was created for detailed Treg investigation. Using the BayesPrism algorithm, Treg scores from TCGA bulk RNA-seq data enabled patient stratification into high and low Treg groups. These findings were further validated through survival analyses across five independent bulk RNA-seq cohorts. We experimentally validated the inhibitory role of Tregs in modulating CD8+ T-cell activity in ovarian cancer.
RESULTS: We conducted an in-depth investigation into the clustering patterns, differentiation trajectories, intercellular interactions, and enrichment profiles of tumor-infiltrating T cells in ovarian cancer. Among the seven functionally defined subclusters (C1-C7), we delineated two distinct "terminal states" of CD4+ T-cell differentiation: FOXP3+ regulatory T cells and STMN1+ proliferative T cells. The OCSCDs dataset comprises seven datasets totaling 137,648 single cells. Using the TCGA dataset, we quantified the proportion of tumor-infiltrating regulatory T cells (Tregs) in OCSCDs through the BayesPrism algorithm and performed survival analyses across five independent bulk RNA-seq datasets from different platforms.
CONCLUSIONS: Our results establish a framework for studying Treg biology in ovarian cancer and these cells may be become an important point in the field of immunotherapy.

Keywords:  CD4+ T cell; Treg cell; ovarian cancer; transcriptome; tumor immune microenvironment

DOI:  https://doi.org/10.3390/biom15091241