bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–04–06
fourteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial.
  2. Neoadjuvant Chemoradiotherapy Enhances Tumor PD-L1 Expression in Pancreatic Cancer.
  3. Changes in tumor-infiltrating lymphocytes and inflammatory blood factors during CRT in rectal cancer.
  4. Multiparametric analysis of tumor infiltrating lymphocytes in solid tumors.
  5. Prognostic significance of CD8 + tumor-infiltrating lymphocytes in operable breast cancer: a meta-analysis.
  6. Role of Lyn Immunohistochemical Staining in Progression of Colorectal Carcinoma.
  7. T-cell receptors identified by a personalized antigen-agnostic screening approach target shared neoantigen KRAS Q61H.
  8. Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer.
  9. The clinical landscape of CAR-engineered unconventional T cells.
  10. KLF2 inhibition expands tumor-resident T cells and enhances tumor immunity.
  11. CD8+ T cell-based immunotherapy: Promising frontier in human diseases.
  12. Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.
  13. Naturally arising memory-phenotype CD4+ T lymphocytes give rise to multiple helper subsets to contribute to tumor immunity while inhibiting GVHD.
  14. 4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8+ T cell antitumor response.
  1. Nat Med. 2025 Apr 01.
    Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial.
    Frank J Lowery, Stephanie L Goff, Billel Gasmi, Maria R Parkhurst, Nivedita M Ratnam, Hyunmi K Halas, Thomas E Shelton, Michelle M Langhan, Aarushi Bhasin, Aaron J Dinerman, Victoria Dulemba, Ian S Goldlust, Alexandra M Gustafson, Abraham A Hakim, Kyle J Hitscherich, Lisa M Kenney, Lior Levy, Juliette G Rault-Wang, Alakesh Bera, Satyajit Ray, Courtney D Seavey, Chuong D Hoang, Jonathan M Hernandez, Jared J Gartner, Sivasish Sindiri, Todd D Prickett, Lori S McIntyre, Sri Krishna, Paul F Robbins, Nicholas D Klemen, Mei Li M Kwong, James C Yang, Steven A Rosenberg.
      Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7-20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4-40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4+ neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121 .
    DOI:  https://doi.org/10.1038/s41591-025-03627-5
  2. Anticancer Res. 2025 Apr;45(4): 1731-1747
    Neoadjuvant Chemoradiotherapy Enhances Tumor PD-L1 Expression in Pancreatic Cancer.
    Kanechika DEN, Takashi Murakami, Ryusei Matsuyama, Kentaro Miyake, Yuki Homma, Yasuhiro Yabushita, Ryutaro Mori, Yukihiko Hiroshima, Ikuma Kato, Itaru Endo.
       BACKGROUND/AIM: Programmed cell death-1 (PD-1) and its ligand PD-L1 play crucial roles in cancer-related immunosuppression. Previous reports have hinted at the potential of neoadjuvant chemoradiotherapy (NACRT) to shift the immunosuppressive microenvironment of pancreatic adenocarcinoma (PDAC) toward an immunogenic state in selected patients. This study aimed to assess the effects of NACRT on PD-L1 expression and PD-1+ lymphocyte infiltration in PDAC.
    PATIENTS AND METHODS: Eighty-two patients with PDAC underwent surgical resection. Among them, 55 patients with borderline-resectable PDAC (BR-PDAC) received NACRT, while 27 patients with resectable PDAC underwent straightforward resection without NACRT. Using immunohistochemical staining, resected specimens were examined to assess PD-1+ tumor-infiltrating lymphocytes (TILs), CD8+ TIL, forkhead box P3 positive (Foxp3+) TILs, and PD-L1 expression in tumor cells.
    RESULTS: High PD-L1 expression correlated positively with NACRT treatment and inversely with PD-1+ TILs. A high CD8+ TILs level was strongly correlated to PD-L1 expression. The numbers of PD-1+ TILs and Foxp3+ TILs were significantly correlated in the straight-line group but not in the NACRT group. In both groups, no significant correlation was found between the overall survival of patients and PD-1+ TILs or PD-L1 expression alone.
    CONCLUSION: NACRT in pancreatic cancer may affect TILs and PD-L1 expression, thereby improving the immunosuppressive microenvironment and implying a potential synergy between checkpoint inhibitors and radiation treatment.
    Keywords:  PD-1; PD-L1; Pancreatic cancer; neoadjuvant chemoradiotherapy; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.21873/anticanres.17554
  3. Oncology. 2025 Mar 28. 1-20
    Changes in tumor-infiltrating lymphocytes and inflammatory blood factors during CRT in rectal cancer.
    Hiroshi Miyakita, Takashi Ogimi, Hajime Kayano, Masaki Mori, Seiichiro Yamamoto.
       INTRODUCTION: Multidisciplinary treatments for advanced rectal cancer are diverse. Neoadjuvant chemoradiation therapy (nCRT) is a total neoadjuvant therapy treatment option. Some studies have reported that tumor-infiltrating lymphocytes (TILs) and inflammatory blood factors [(neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune inflammatory index (SII)] are predictors of nCRT efficacy. However, the relationship between changes in TILs and inflammatory blood factors during nCRT and the resulting tumor regression grade (TRG) remains unclear. In this study, we investigated whether changes in TILs and inflammatory blood factors during nCRT were related to TRG.
    METHODS: We retrospectively studied 196 patients with rectal cancer who underwent curative resection after nCRT for advanced rectal cancer. Immunohistochemical staining of lymphocyte surface markers, including CD3, CD4, and CD8, was performed on biopsy specimens before and during nCRT. Inflammatory blood factors were assessed using blood samples collected before treatment and seven days after the initiation of nCRT.
    RESULTS: Changes in CD4 levels were related to TRG. NLR and SII during nCRT were associated with TRG. TRG tended to be better in patients with values below the cut-off. The NLR during nCRT and changes in NLR, PLR, and SII were associated with the tumor shrinkage rate. Changes in PLR were related to TRG. There was no relationship between TIL, peripheral blood changes, and recurrence rate.
    CONCLUSION: It was suggested that changes in CD4+ TILs immediately after treatment initiation and changes in inflammatory blood factors during treatment may be useful for predicting the reduction rate and TRG. These changes begin early during treatment and may be useful in predicting efficacy.
    DOI:  https://doi.org/10.1159/000545312
  4. Methods Cell Biol. 2025 ;pii: S0091-679X(23)00080-8. [Epub ahead of print]195 39-70
    Multiparametric analysis of tumor infiltrating lymphocytes in solid tumors.
    Rebecca Borella, Annamaria Paolini, Beatrice Aramini, Lara Gibellini, Valentina Masciale, Domenico Lo Tartaro, Massimo Dominici, Sara De Biasi, Andrea Cossarizza.
      The use of single-cell technologies in characterizing the interactions between immune and cancer cells is in continuous expansion. Indeed, the combination of different single-cell approaches enables the definition of novel phenotypic and functional aspects of the immune cells infiltrating the tumor microenvironment (TME). This approach is promoting the discovery of relevant and reliable predictive biomarkers, along with the development of new promising treatments. In this chapter, we describe the main subsets of tumor-infiltrating lymphocytes from a phenotypical and functional point of view and discuss the use of single-cell technologies used to characterize these cell populations within TME.
    Keywords:  Flow cytometry; Immune checkpoint proteins; Single-cell technologies; Tumor infiltrating lymphocytes; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.mcb.2023.03.006
  5. BMC Cancer. 2025 Apr 02. 25(1): 601
    Prognostic significance of CD8 + tumor-infiltrating lymphocytes in operable breast cancer: a meta-analysis.
    Ruijie Niu, Cheng Wang, Yiqun Xie, Shuangshuang Li, Qian Zhao, Yuqing Chang, Zubing Mei.
       BACKGROUND: As key mediators of antitumor immunity, CD8 + tumor-infiltrating lymphocytes present antigens and initiate robust immune responses against cancer cells. When stratified by location, CD8 + T lymphocytes were counted and classified as intratumoral, stromal, or total CD8 + tumor-infiltrating lymphocytes. Despite their crucial role, the impact, especially the specific type of CD8 + T lymphocytes on breast cancer prognosis remains controversial. This meta-analysis synthesized evidence to delineate the relationship between CD8 + tumor-infiltrating lymphocytes density of different counting methods and breast cancer patient outcomes.
    METHODS: PubMed, Embase, and the Cochrane Library were systemically searched from inception through January 2024 for studies evaluating the prognostic significance of CD8 + tumor-infiltrating lymphocytes in breast cancer. The primary endpoint was disease-free survival (DFS), and the second endpoints were overall survival (OS), breast cancer-specific survival (BCSS), and recurrence-free survival (RFS).
    RESULTS: Thirty-four studies encompassing 23,626 breast cancer patients were included. Pooled hazard ratios (HRs) indicated a significant association of high CD8 + TIL presence with improved DFS (HR = 0.63; 95% CI = 0.54-0.73), OS (HR = 0.72; 95% CI = 0.65-0.79), BCSS (HR = 0.67; 95% CI = 0.58-0.78), and RFS (HR = 0.53; 95% CI = 0.38-0.73). Stratification by TIL location (intratumoral [iCD8], stromal [sCD8], or total [tCD8]) did not significantly impact DFS or OS.
    CONCLUSION: High CD8 + TIL density in breast cancer patients is correlated with a favorable prognosis, irrespective of the location of CD8 + tumor-infiltrating lymphocytes. These findings affirm the prognostic utility of CD8 + TIL assessment and may guide future immunotherapeutic strategies.
    Keywords:  Breast cancer; CD8; Meta-analysis; Prognosis; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1186/s12885-025-13912-8
  6. Asian Pac J Cancer Prev. 2025 Mar 01. pii: 91572. [Epub ahead of print]26(3): 943-948
    Role of Lyn Immunohistochemical Staining in Progression of Colorectal Carcinoma.
    Hany Y Sayed, Reda F Abdelmeguid, Dalia M Abd El-Rehim, Nisreen A A Osman, Nisreen Dm Toni.
       OBJECTIVE: To investigate the immunohistochemical expression of Lyn in colorectal adenocarcinoma with its corresponding lymph node metastasis and correlation with clinicopathological characteristics.
    METHODS: Immunohistochemical analysis of Lyn expression was performed on 70 colorectal cancer (CRC) tissue specimens of hemicolectomy and their corresponding lymph node metastases. Clinicopathological data, including age, gender, tumor size, location, TNM stage, modified Dukes stage, tumor grade, tumor-infiltrating lymphocytes (TILs), poorly differentiated clusters (PDCs), vascular invasion, and perineural invasion (PNI), were collected and analyzed to assess correlations with Lyn expression.
    RESULTS: High Lyn expression was observed in 34.3% of CRC cases. Significant associations were found between high Lyn expression and positive nodal metastasis (p < 0.001), higher TNM stage (p = 0.003), and advanced modified Dukes stage (p = 0.001). No significant associations were found between Lyn expression and age, gender, tumor size, primary tumor location, tumor grade, TILs, PDCs, vascular invasion, or PNI (p > 0.05 for all). A significant correlation was observed between Lyn expression in primary tumors and their corresponding lymph node metastases (p = 0.033).
    CONCLUSION: Lyn expression is significantly associated with unfavorable clinicopathological parameters, which are lymph node metastasis and advanced tumor stage, suggesting its potential role as a prognostic marker in colorectal cancer.
    Keywords:  Colorectal cancer (CRC); Lyn; Prognosis; immunohistochemical
    DOI:  https://doi.org/10.31557/APJCP.2025.26.3.943
  7. Front Immunol. 2025 ;16 1509855
    T-cell receptors identified by a personalized antigen-agnostic screening approach target shared neoantigen KRAS Q61H.
    Volker Lennerz, Christoph Doppler, Martina Fatho, Anja Dröge, Sigrid Schaper, Kristin Gennermann, Nadine Genzel, Stephanie Plassmann, David Weismann, Samuel W Lukowski, Dominik Bents, Christina Beushausen, Karen Kriese, Hermann Herbst, Volkhard Seitz, Rudolf Hammer, Paul J Adam, Stephan Eggeling, Catherine Wölfel, Thomas Wölfel, Steffen Hennig.
      Adoptive cell therapy (ACT) with TCR-engineered T-cells represents a promising alternative to TIL- or CAR-T therapies for patients with advanced solid cancers. Currently, selection of therapeutic TCRs critically depends on knowing the target antigens, a condition excluding most patients from treatment. Direct antigen-agnostic identification of tumor-specific T-cell clonotypes and TCR-T manufacturing using their TCRs can advance ACT for patients with aggressive solid cancers. We present a method to identify tumor-specific clonotypes from surgical specimens by comparing TCRβ-chain repertoires of TILs and adjacent tissue-resident lymphocytes. In six out of seven NSCLC-patients analyzed, our selection of tumor-specific clonotypes based on TIL-abundance and high tumor-to-nontumor frequency ratios was confirmed by gene expression signatures determined by scRNA-Seq. In three patients, we demonstrated that predicted tumor-specific clonotypes reacted against autologous tumors. For one of these patients, we engineered TCR-T cells with four candidate tumor-specific TCRs that showed reactivity against the patient's tumor and HLA-matched NSCLC cell lines. The TCR-T cells were then used to screen for candidate neoantigens and aberrantly expressed antigens. Three TCRs recognized recurrent driver-mutation KRAS Q61H-peptide ILDTAGHEEY presented by HLA-A*01:01. The TCRs were also dominant in a tumor relapse, one was found in cell free DNA. The finding of homologous TCRs in independent KRAS Q61H-positive cancers suggests a therapeutic opportunity for HLA-matched patients with KRAS Q61H-expressing tumors.
    Keywords:  KRAS Q61H; T-cell receptor (TCR); TCR-T cell; cancer immunotherapy; immune-oncology; neoantigen; oncogenic driver gene; tumor-specific antigen
    DOI:  https://doi.org/10.3389/fimmu.2025.1509855
  8. Mol Ther. 2025 Mar 27. pii: S1525-0016(25)00216-3. [Epub ahead of print]
    Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer.
    Neil Carleton, Aaron B I Rosen, Jishnu Das, Michael T Lotze.
      Immuno-oncology (IO) has had over a century to develop from the original seminal insights of Virchow in 1863, seeing inflammation and lymphoid infiltrates as a common anlage for many adult tumors. That IO has become a central pillar of cancer treatment has come about because of the remarkable clinical and subsequent commercial success of immune checkpoint blockade (ICB) in the last fifteen years. This as well includes now approved cell and gene therapies for patients with cancer including an armed adenovirus, oncolytic herpes virus, and adoptive transfer of dendritic cells, chimeric antigen receptor T cells (CAR-T), and tumor infiltrating lymphocytes (TILs). The evolution of such applications required the stepwise development of a deeper understanding of the molecular biology of cancer and the physiology of immunobiology. This also recapitulates, in a broader sense, our evolutionary trajectory with capture of 'evolvability', not only across the development of species, but also within individuals. This review covers how our foundational understanding of immune system learning and evolvability have facilitated better understanding of the co-evolutionary interactions between the epithelium and immune system. We highlight examples of this in breast, colon, prostate, pancreas, and lung cancer, and provide examples of next-generation cell and gene therapies that intercept cancer development.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.042
  9. Trends Cancer. 2025 Mar 27. pii: S2405-8033(25)00069-X. [Epub ahead of print]
    The clinical landscape of CAR-engineered unconventional T cells.
    Yan-Ruide Li, Yichen Zhu, Yuning Chen, Lili Yang.
      Unconventional T cells, such as invariant natural killer T (iNKT), γδ T, and mucosal-associated invariant T (MAIT) cells, play a pivotal role in bridging innate and adaptive immunity. Their capacity for rapid tumor targeting and effective modulation of the tumor microenvironment (TME) makes them promising candidates for cancer immunotherapy. Advances in chimeric antigen receptor (CAR) engineering have further highlighted their therapeutic potential, particularly for treating challenging cancers. Notably, these cells exhibit favorable safety profiles, enhancing their viability as off-the-shelf therapeutic options. We provide a comprehensive analysis of the clinical applications of CAR-engineered unconventional T cells, focusing on genetic modifications, manufacturing processes, preconditioning regimens, and dosing strategies. We discuss successful examples from recent clinical trials and explore future directions for utilizing these cells in cancer therapy and beyond.
    Keywords:  cancer immunotherapy; chimeric antigen receptor engineering; invariant natural killer T cell; mucosal-associated invariant T cell; unconventional T cell; γδ T cell
    DOI:  https://doi.org/10.1016/j.trecan.2025.03.001
  10. Res Sq. 2025 Mar 13. pii: rs.3.rs-5966555. [Epub ahead of print]
    KLF2 inhibition expands tumor-resident T cells and enhances tumor immunity.
    Eli Gilboa, Vineet Gupta, Darija Muharemagic, Sunwoo Ham, Erietta Stelekati, Emily Clark.
      Tissue resident memory CD8+ T cells (Trm) constitute a distinct population of non-circulating memory T cells1-5 vastly exceeding the number of circulating T cells5, and play a pivotal role in protective immunity against pathogens6-8. How to promote the generation of vaccine specific Trm remains an important challenge. Whether Trm contribute also to immune control of tumors or just correlate with an unrelated process linked to clinical outcome has not been unequivocally established9,10, and phenotypic markers such as co-expression of CD69 and CD103 or CD49a integrins commonly used to monitor tumor infiltrating Trm do not unambiguously define this subset. Here we tested the hypothesis that transient downregulation of KLF2, the most conserved feature of Trm ontogeny4,11,12, will promote the differentiation of vaccine activated CD8+ T cells into Trm and enhance antitumor immunity. We show that 4-1BB antibody targeted delivery of a KLF2 siRNA to tumor bearing mice led to the downregulation of KLF2 in vaccine activated CD8+ T cells and the accumulation of phenotypically defined intratumoral CD69+CD103+ and CD69+CD49a+ CD8+ T cells which correlated with enhanced control of tumor growth. This study could serve as the foundation of a broadly applicable and clinically useful way to promote the generation of vaccine specific Trm and provides direct evidence that intratumoral CD8+CD69+CD103+ and CD8+CD69+CD49a+ cells are indeed Trm and that Trm contribute to tumor immunity.
    DOI:  https://doi.org/10.21203/rs.3.rs-5966555/v1
  11. Biochem Pharmacol. 2025 Apr 01. pii: S0006-2952(25)00171-6. [Epub ahead of print] 116909
    CD8+ T cell-based immunotherapy: Promising frontier in human diseases.
    Nu Quynh Chau Ton, Gitima Deka, Pil-Hoon Park.
      The abundant cell components of the adaptive immune system called T lymphocytes (T cells) play important roles in mediating immune responses to eliminate the invaders and create the memory of the germs to form a new immunity for the next encounter. Among them, cytotoxic T cells expressing cell-surface CD8 are the most critical effector cells that directly eradicate the target infected cells by recognizing antigens presented by major histocompatibility complex class I molecules to protect our body from pathological threats. In the continuous evolution of immunotherapy, various CD8+ T cell-based therapeutic strategies have been developed based on the role and molecular concept of CD8+ T cells. The emergence of such remarkable therapies provides promising hope for multiple human disease treatments such as autoimmunity, infectious disease, cancer, and other non-infectious diseases. In this review, we aim to discuss the current knowledge on the utilization of CD8+ T cell-based immunotherapy for the treatment of various diseases, the molecular basis involved, and its limitations. Additionally, we summarize the recent advances in the use of CD8+ T cell-based immunotherapy and provide a comprehensive overview of CD8+ T cells, including their structure, underlying mechanism of function, and markers associated with CD8+ T cell exhaustion. Building upon these foundations, we delineate the advancement of CD8+ T cell-based immunotherapies with fundamental operating principles followed by research studies, and challenges, as well as illustrate human diseases involved in this development.
    Keywords:  CD8(+) T cell; Exhaustion; Immunotherapy; Lymphocytes
    DOI:  https://doi.org/10.1016/j.bcp.2025.116909
  12. J Extracell Vesicles. 2025 Apr;14(4): e70035
    Direct delivery of immune modulators to tumour-infiltrating lymphocytes using engineered extracellular vesicles.
    Xiabing Lyu, Tomoyoshi Yamano, Kanto Nagamori, Shota Imai, Toan Van Le, Dilireba Bolidong, Makie Ueda, Shota Warashina, Hidefumi Mukai, Seigo Hayashi, Kazutaka Matoba, Taito Nishino, Rikinari Hanayama.
      Extracellular vesicles (EVs) are important mediators of cell-cell communication, including immune regulation. Despite the recent development of several EV-based cancer immunotherapies, their clinical efficacy remains limited. Here, we created antigen-presenting EVs to express peptide-major histocompatibility complex (pMHC) class I, costimulatory molecule and IL-2. This enabled the selective delivery of multiple immune modulators to antigen-specific CD8+ T cells, promoting their expansion in vivo without severe adverse effects. Notably, antigen-presenting EVs accumulated in the tumour microenvironment, increasing IFN-γ+ CD8+ T cell and decreasing exhausted CD8+ T cell numbers, suggesting that antigen-presenting EVs transformed the 'cold' tumour microenvironment into a 'hot' one. Combination therapy with antigen-presenting EVs and anti-PD-1 demonstrated enhanced anticancer immunity against established tumours. We successfully engineered humanized antigen-presenting EVs, which selectively stimulated tumour antigen-specific CD8+ T cells. In conclusion, engineering EVs to co-express multiple immunomodulators represents a promising method for cancer immunotherapy.
    Keywords:  antigen presentation; cancer immunotherapy; drug delivery; extracellular vesicle; targeted cytokine delivery
    DOI:  https://doi.org/10.1002/jev2.70035
  13. Cancer Immunol Res. 2025 Apr 01.
    Naturally arising memory-phenotype CD4+ T lymphocytes give rise to multiple helper subsets to contribute to tumor immunity while inhibiting GVHD.
    Ziying Yang, Jing Li, Hideaki Watanabe, Feng Gao, Akihisa Kawajiri, Keita Koinuma, Kosuke Sato, Yuko Okuyama, Shunichi Tayama, Yoichiro Iwakura, Naoto Ishii, Takeshi Kawabe.
      Memory-phenotype (MP) CD4+ T lymphocytes spontaneously develop in steady state from peripheral naïve precursors in a manner dependent on self-antigen recognition. While MP cells possess innate type 1 and 3 effector functions that can contribute to host defense and autoimmunity, their immunological functions in tumor immunity and graft-versus-host disease (GVHD), which results from therapeutic bone marrow transplantation (BMT) against hematological malignancies, remain unclear. Here we show that in mixed lymphocyte reactions, MP lymphocytes can generate T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cell subsets, whereas naïve cells dominantly differentiate to Th1. Consistent with this, naïve lymphocytes mainly induce Th1 responses in the mouse EL4 model of malignant lymphoma and the B16 model of malignant melanoma, whereas MP cells efficiently give rise to Th1, Th17, and Treg subsets to exert mild, IFN--dependent antitumor activities in vivo. Moreover, we demonstrate using a mouse model of BMT that MP cells more efficiently differentiate into Treg cells to partially suppress GVHD as compared to naïve T lymphocytes. Furthermore, our data suggest that when used as donor T lymphocytes in BMT in tumor-bearing mice, MP cells give rise to Th1, Th17, and Treg cells to generate antitumor responses without inducing GVHD. Together these results identify MP cells as a unique T-cell population that has potential to generate multiple T helper subsets including Th1 and Treg cells, thereby contributing to tumor immunity while inhibiting development of BMT-associated GVHD.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0598
  14. J Clin Invest. 2025 Apr 03. pii: e190841. [Epub ahead of print]
    4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8+ T cell antitumor response.
    Jihae Ahn, Ping Xie, Siqi Chen, Guilan Shi, Jie Fan, Minghui Zhang, Hui Tang, Amanda R Zuckerman, Deyu Fang, Yong Wan, Timothy M Kuzel, Yi Zhang, Bin Zhang.
      Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor responses of CD8 T cells. However, the underlying in-depth mechanisms remain to be defined. Here, we show that agonistic 4-1BB treatment of activated CD8+ T cells under continuous antigenic stimulation are more metabolically vulnerable to redox perturbation by ablation of intracellular glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibition. Further, genetic deletion of adenosine A2B receptor (A2BR) induces superior survival and expansion advantage of competent CD8+ T cells with agonistic 4-1BB costimulation, leading to more effective antitumor efficacy of adoptive cell therapy (ACT). Mechanistically, A2BR deletion helps sustain the increased energy and biosynthetic requirements through the GSH-GPX4 axis upon 4-1BB costimulation. A2BR deletion in combination with agonistic 4-1BB costimulation displays a greater ability to promote antitumor CD8+ effector T cell survival and expansion while mitigating T cell exhaustion. Thus, the A2BR pathway plays an important role in metabolic reprogramming with potentiation of the GSH-GPX4 cascade upon agonistic 4-1BB costimulation that allows the fine-tuning of the antitumor responses of CD8+ T cells.
    Keywords:  Adaptive immunity; Immunology; Immunotherapy; Oncology; T cells
    DOI:  https://doi.org/10.1172/JCI190841
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒06 at 6:05.