bims-tuinly 2025-10-12 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–10–12
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Tumor-infiltrating lymphocytes-derived CD8+ clonotypes infiltrate the tumor tissue and mediate tumor regression in glioblastoma.
Recent advances in adoptive cell therapy for cancer immunotherapy.
Collagen-disrupting attIL12 TIL therapy boosts deep T cell infiltration via dual signaling activation and CCKAR reduction in sarcomas.
Prognostic value of visually and computationally-assessed tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer (TBCRC-030).
CD8+ TILs in necrotic tumors after neoadjuvant immunochemotherapy predict outcomes in non-small-cell lung cancer patients.
HLA-DR expression in cytotoxic T lymphocytes: a key to boost the therapeutic potential of T cell-based strategies for breast cancer.
Nanomedicine-mediated co-expression of a PD-1 blockade agent and CXCL9 synergizes T cell infiltration and activation in solid tumors.
Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.
The role of TCF-1+CD8+ exhausted progenitors and TCF-1 in graft-versus-host responses.
Targeting organelle function in T cells for cancer immunotherapy.

Oncoimmunology. 2025 Dec;14(1): 2559784

Tumor-infiltrating lymphocytes-derived CD8+ clonotypes infiltrate the tumor tissue and mediate tumor regression in glioblastoma.

Lucas C M Arruda, Julia Karbach, Dragan Kiselicki, Hans-Michael Altmannsberger, Evgueni Sinelnikov, Dirk Gustavus, Hans Hoffmeister, Akin Atmaca, Elke Jäger.

  Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated consistent clinical efficacy in treating advanced melanoma and other "hot" tumors. However, it has shown limited success in "cold" tumors like glioblastoma. We present the successful treatment of a rapidly progressing glioblastoma patient with TILs expanded using a defined cytokine combination of IL-2, IL-15, and IL-21. The patient received lymphodepletion with cyclophosphamide one day pre-TIL infusion, followed by a single dose of IL-2 post-transfer. Complete tumor regression was observed after two TIL infusions administered two weeks apart. The TIL products were enriched for CD8+ T-cells and demonstrated specific lysis of the autologous tumor cell line. Transcriptomic analysis of tumor biopsies post-TIL infusion revealed increased expression of genes associated with immunological synapse formation and T-cell effector function, correlating with the patient's clinical outcome. T-cell receptor (TCR) next-generation sequencing of the infused TILs and post-treatment tumor biopsies confirmed the infiltration and expansion of TIL-derived clonotypes within the tumor microenvironment. CD8+ T-cell clonotypes exhibited robust tumor migration and expansion, while CD4+ T-cells showed limited tumor infiltration. In conclusion, TILs expanded with IL-2/IL-15/IL-21 represent a promising therapeutic approach for glioblastoma, overcoming traditional challenges posed by the tumor microenvironment and achieving significant clinical outcomes.

Keywords:  Glioblastoma; IL-15; IL-2; IL-21; cytotoxic T- cells; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1080/2162402X.2025.2559784
Front Immunol. 2025 ;16 1665488

Recent advances in adoptive cell therapy for cancer immunotherapy.

Jiameng Qian, Yuhua Liu.

  Adoptive cell therapy (ACT), a key direction in tumor immunotherapy, has achieved remarkable progress in recent years. This paper systematically reviews the current status and future trends of ACT, covering lymphokine-activated killer cells (LAK), tumor-infiltrating lymphocytes (TIL), cytokine-induced killer cells (CIK), dendritic cells (DC), T cell receptor-modified T cells (TCR-T), chimeric antigen receptor T cells (CAR-T), natural killer (NK) cells, chimeric antigen receptor-modified NK cells (CAR-NK), and the emerging CAR-M. The paper focuses on emerging technological approaches, including universal CAR structural optimization, iPSC-derived cell products, multifunctional CAR design, and AI-assisted antigen screening. It also compares differences among various cell therapies in antigen specificity, efficacy persistence, safety, and clinical application challenges. The core contribution of this paper lies in synthesizing recent research advances to propose strategies for addressing tumor heterogeneity, antigen escape, cell persistence, and therapeutic safety in ACT. This provides a reference for future personalized and precision cell therapy approaches.

Keywords:  CAR-M; CAR-NK; iPSC-derived cells; macrophage engineering; next-generation ACT

DOI:  https://doi.org/10.3389/fimmu.2025.1665488
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2507542122

Collagen-disrupting attIL12 TIL therapy boosts deep T cell infiltration via dual signaling activation and CCKAR reduction in sarcomas.

Jiemiao Hu, Harjeet Singh, Yining Jin, Wendong Zhang, Jian Wang, Xueqing Xia, Neeta Somaiah, Richard Gorlick, Shulin Li.

  Tumor-targeted T cell therapies of various types have been booming, but T cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell-surface vimentin (CSV)-targeted and membrane-anchored interleukin 12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, but fail to reduce collagen expression by tumor cells, resulting in resistance to attIL12-T cell treatment. In this study, we found that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells by attIL12-TILs overcomes resistance to attIL12-T cell treatment and required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and human leukocyte antigen-T cell receptor on attIL12-TILs; When either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells induced interferon gamma production synergistically, which in combination with CCKAR downregulation reduced collagen expression through suppression of both transforminggrowth factor beta-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T cell infiltration and improved tumor growth inhibition in PDX sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T cell infiltration in high-grade, collagen-rich tumors.

Keywords:  CCKAR; T cell infiltration; attIL12-TIL; collagens; sarcoma PDX

DOI:  https://doi.org/10.1073/pnas.2507542122
J Natl Cancer Inst. 2025 Oct 11. pii: djaf289. [Epub ahead of print]

Prognostic value of visually and computationally-assessed tumor-infiltrating lymphocytes in early-stage triple-negative breast cancer (TBCRC-030).

Guilherme Nader-Marta, Xiangying Chu, Satabhisa Mukhopadhyay, Vandana G Abramson, Adam Brufsky, Erica Michelle Stringer-Reasor, Susan Faye Dent, Tiffany A Traina, Lisa A Carey, Mothaffar F Rimawi, Jennifer M Specht, Kathy D Miller, Cesar Augusto Santa-Maria, Tathagata Dasgupta, Busem Binboğa Kurt, Michelle DeMeo, Ian E Krop, Nadine M Tung, Stuart J Schnitt, Nabihah Tayob, Erica L Mayer.

   BACKGROUND: Tumor-infiltrating lymphocytes (TILs), assessed by visual examination (VE), are prognostic and predictive in early-stage triple-negative breast cancer (TNBC). Computational assessment (CA) may provide a complementary approach. We evaluated the prognostic value of TILs by VE and CA.
METHODS: TBCRC 030 was a randomized phase II trial enrolling patients with BRCA1/2-proficient stage I-III TNBC to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathologic response at surgery. TILs were visually scored on digitized pre-treatment biopsies per International TILs Working Group recommendations. CA used the 4D QPOR platform to generate TILs, immune heterogeneity index (IHI), and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden (RCB) 0/1 was assessed using ROC curves and odds ratios (ORs) with 95% CIs; all statistical tests were two-sided.
RESULTS: Of 139 response-evaluable patients, 121 had matched VE and CA data (59 cisplatin, 62 paclitaxel). Median VE TILs were higher in responders (40.0% vs. 10.0%, p = .002) and predicted response (OR 1.86, 95% CI 1.24-2.87, AUC 0.69, 95% CI 0.57-0.80). CA CmbI differed by response group and predicted RCB 0/1 (OR 3.20, 1.05-11.07; AUC 0.62, 0.51-0.73). CA TILs and IHI were not predictive. VE TILs and CA CmbI predicted response to paclitaxel (OR 2.91, 1.56-6.14; OR 9.17, 2.01-66.39, respectively), but not to cisplatin.
CONCLUSION: VE TILs and CA CmbI were each associated with response to NAC in TNBC in the overall cohort and the paclitaxel arm. CA CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.

Keywords:  biomarker; computational assessment; immune microenvironment; triple-negative breast cancer; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1093/jnci/djaf289
Signal Transduct Target Ther. 2025 Oct 09. 10(1): 335

CD8+ TILs in necrotic tumors after neoadjuvant immunochemotherapy predict outcomes in non-small-cell lung cancer patients.

Haifeng Lin, Yi Han, Lei Guo, Caigang Liu, Hefei Li, Jie Li, Chong Wang, Lijuan Zhou, Xiangna Zhang, Lisha Sun, Ying Yi Zhang, Xiaojing Chu, Jianquan Shi, Xiaoqing Cao, Yifang Chen, Zhiqing Qin, Jiaming Bao, Shiya Wan, Hao Chen, Xiaoran Tang, Xiang Li, Xinyu Wang, Yuting Cheng, Yixia Li, Jie Zhang, Chang Liu, Xuguang Zhang, Yanan Wang, Yi Hu, Nanying Che, Xiaowei Xu, Hezhe Lu.

Neoadjuvant immunochemotherapy has shown promising results, with major pathologic response (MPR, ≤10% residual viable tumors [RVT]) as the primary outcome. However, %RVT showed limited predictive power in stratifying outcomes within the MPR and non-MPR groups. To identify a better prognostic marker, this study analyzed 200 non-small-cell lung cancer (NSCLC) samples after neoadjuvant PD-1 blockade combined with chemotherapy across three medical centers. Among these patients, 99 had necrotic regions in their residual lesions. We found that tumor-infiltrating lymphocytes in necrotic areas (nTILs) lose their cellular structure, but retained T-cell-specific antigens, making them detectable by immunohistochemistry. Regardless of PD-L1 status or lymph node metastasis, patients with high CD8+ nTIL density had significantly improved event-free survival (EFS) (hazard ratio [HR]: 0.08; 95% CI: [0.01-0.62]; p = 0.0019). Furthermore, CD8+ nTIL density improved prognostic predictions for patients within the MPR (p = 0.017) and non-MPR groups (p = 0.076). Radiological responses did not correlate with MPR, CD8+ nTIL density or EFS. 41.5% MPR cases were misclassified by radiological assessments. When compared with radiographic response and pathological response, CD8+ nTIL density outperformed these traditional parameters in approximating EFS. These findings demonstrate that the CD8+ nTIL density is a robust predictor of EFS in NSCLC patients treated with neoadjuvant immunochemotherapy and has great potential in guiding treatment decisions.

DOI: https://doi.org/10.1038/s41392-025-02435-0
Front Immunol. 2025 ;16 1653970

HLA-DR expression in cytotoxic T lymphocytes: a key to boost the therapeutic potential of T cell-based strategies for breast cancer.

Rute Salvador, Bruna Filipa Correia, Daniela Grosa, Telma Martins, Suelen Cristina Soares Baal, Diana Pereira Saraiva, Sofia Cristóvão-Ferreira, Isabel Lopes Pereira, Cátia Rebelo de Almeida, Rita Fior, Antonio Jacinto, Carolina Mathias, Sofia Braga, M Guadalupe Cabral.

  T cell-based therapies, involving ex vivo expansion of patients' T lymphocytes, hold significant promise for chemotherapy resistant cases of breast cancer (BC), although their effectiveness remains challenging. Building on our previous findings that the expression of the antigen presenting molecule, HLA-DR, is crucial on tumor-infiltrating cytotoxic T lymphocytes (CTLs) for a favorable response to neoadjuvant chemotherapy, we further investigated the role of HLA-DR-expressing CTLs in anti-tumor responses and evaluated strategies to amplify these cells. Through in vitro and in vivo experiments, we demonstrated that HLA-DR expression on CTLs is important for effective tumor cell elimination. Notably, blocking HLA-DR or depleting CD4+ T cells impaired CTLs activation, suggesting a critical role for antigen presentation by CTLs to CD4+ T cells through HLA-DR in promoting robust anti-tumor responses. Based on these findings we optimized an ex vivo stimulation protocol that increases the proportion of HLA-DR+CTLs with improved cytotoxicity, prioritizing cell quality over yield. Moreover, we showed that adding anti-PD-1 to the stimulation, further upregulated HLA-DR expression, and intensified CTLs' cytotoxic ability. This aligns with our in silico analysis suggesting a potential regulatory link between PD-1 and HLA-DR via non-coding RNAs. Overall, our findings open new avenues for advancing T cell-based therapies and improve the outcomes of chemotherapy-resistant-BC.

Keywords:  3D co-cultures; adoptive T cell therapy; breast cancer; cytotoxic T lymphocytes; cytotoxicity; immunomodulation; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1653970
Biomater Sci. 2025 Oct 07.

Nanomedicine-mediated co-expression of a PD-1 blockade agent and CXCL9 synergizes T cell infiltration and activation in solid tumors.

Yan Wang, Liang Zhao, Jia-Yu Luo, Jie Li, Xin-Ya Gao, Hui-Xiao Li, Yue Zheng, Jia-Wei Liu.

Considerable progress has been made in cancer immunotherapy with the use of immune checkpoint blockade (ICB). However, its clinical efficacy remains limited due to poor T cell infiltration in solid tumors. Here, we engineered a co-expression plasmid-based gene nanomedicine to drive tumor cells to simultaneously secrete the single-chain variable fragment of an antibody targeting programmed cell death protein 1 (αPD-1 scFv, a PD-1 blocking agent) and C-X-C Motif Chemokine Ligand 9 (CXCL9, a T cell chemokine). The gene nanomedicine showed a synergistic effect on enhancing the migration and the cytotoxicity of CD8+ T cells in vitro and in vivo. With its dual functions, the growth of subcutaneous melanoma was effectively inhibited, and the survival time of melanoma-bearing mice was prolonged. This study provides a synergistic strategy for improving the therapeutic efficacy of immune checkpoint blockade through nanoparticle-delivered nucleic acid drugs to modulate the tumor microenvironment.

DOI: https://doi.org/10.1039/d5bm01105a
JCI Insight. 2025 Oct 08. pii: e191220. [Epub ahead of print]10(19):

Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.

Amir Yousif, Abbey A Saadey, Ava Lowin, Asmaa M Yousif, Ankita Saini, Madeline R Allison, Kelley Ptak, Eugene M Oltz, Hazem E Ghoneim.

  Epigenetic scarring of terminally dysfunctional (TDysf) CD8+ T cells hinders long-term protection and response to immune checkpoint blockade during chronic infections and cancer. We developed a faithful in vitro model for CD8+ T cell terminal dysfunction as a platform to advance T cell immunotherapy. Using TCR-transgenic CD8+ T cells, we found that 1-week peptide stimulation, mimicking conditions in previous models, failed to induce a stable exhaustion program. In contrast, prolonged stimulation for 2-3 weeks induced T cell dysfunction but triggered activation-induced cell death, precluding long-term investigation of exhaustion programs. To better mimic in vivo exhaustion, we provided post-effector, chronic TGF-β1 signals, enabling survival of chronically stimulated CD8+ T cells for over 3 weeks. These conditions induced a state of terminal dysfunction, marked by a stable loss of effector, cytotoxicity, and memory programs, along with mitochondrial stress and impaired protein translation. Importantly, transcriptomic and epigenetic analyses verified the development of terminal exhaustion-specific signatures in TDysf cells. Adoptive transfer of TDysf cells revealed their inability to recall effector functions or proliferate after acute lymphocytic choriomeningitis virus rechallenge. This tractable model system enables investigation of molecular pathways driving T cell terminal dysfunction and discovery of therapeutic targets for cancer or chronic infections.

Keywords:  Adaptive immunity; Cancer immunotherapy; Epigenetics; Immunology; Oncology

DOI:  https://doi.org/10.1172/jci.insight.191220
JCI Insight. 2025 Oct 08. pii: e181568. [Epub ahead of print]10(19):

The role of TCF-1+CD8+ exhausted progenitors and TCF-1 in graft-versus-host responses.

Kevin Quann, Faruk Sacirbegovic, Sarah Rosenberger, Emily R McFerran, Kentin C Codispot, Laura Garcia-Dieguez, Alexander M Rowe, Wenzhong Wei, Dhanpat Jain, Jennifer M McNiff, Warren Shlomchik.

  In allogeneic hematopoietic transplantation, donor αβ T cells attack recipient tissues, causing graft versus host disease (GVHD). A longstanding question has been how GVHD is maintained despite T cell exhaustion from chronic alloantigen stimulation. In other exhaustion models, CD8 responses are sustained by CD39loTim-3loToxhiTCF-1hi precursor exhausted T cells (TPEX). Here we characterize CD8+ TPEX in the B6(H-2b)→129(H-2b) GVHD model wherein responses against the minor histocompatibility antigen H60 can be tracked using MHCI-tetramers (TetH60). Early after transplant, TetH60+ CD8 cells were uniformly PD-1hiToxhi, whereas TetH60- cells also had PD-1loToxlo cells, indicative of more diverse antigen experiences. Among TetH60+ and TetH60- populations were CD39loTCF-1hi cells. Upon competitive retransplantation, TetH60+CD39loTCF-1hi cells outcompeted TetH60+CD39hiTCF-1lo cells and underwent self-renewal, whereas CD39hiTCF-1lo cells did not yield TCF-1hi cells. To test the role of TCF-1, we studied CD8 cells lacking long TCF-1 isoforms (p45-/-). P45-/- cells were outcompeted by WT cells when transplanted into 129 recipients, though they expanded similarly in syngeneic recipients. In the B6→C3H.SW(H-2b) model, p45-/- CD8 cells caused less weight loss than did WT CD8 cells; however, histopathologic GVHD was similar in both groups. P45-/- and WT CD8 cells also had similar graft versus leukemia activity. These results highlight the complex biology of TCF-1 in supporting alloreactive T cell function.

Keywords:  Adaptive immunity; Bone marrow transplantation; Immunology; T cells; Transplantation

DOI:  https://doi.org/10.1172/jci.insight.181568
Nat Rev Immunol. 2025 Oct 09.

Targeting organelle function in T cells for cancer immunotherapy.

Jeremy G Baldwin, Christoph Heuser-Loy, Luca Gattinoni.

Organelles are the internal batteries, gears, actuators, 3D printers and transmitters that drive cell function. Their composition and activity vary between cell types depending on functional demands. In T cells, which are key mediators of immunosurveillance and tumour eradication, organelles are relatively few and function at basal levels when cells are at rest. However, upon activation, they increase in number and size and undergo extensive remodelling to support rapid proliferation, effector differentiation and adaptation to diverse microenvironments, including the tumour microenvironment, thereby enabling efficient clearance of target cells. In this Review, we provide an overview of recent advances in our understanding of how various organelles contribute to T cell-mediated antitumour immunity. We also discuss emerging strategies to modulate organelle functions - from organelle-targeted therapies and their use as cargo delivery systems to the transfer or transplantation of native or synthetic organelles - that have the potential to enhance cancer immunotherapies involving immune-checkpoint blockade or the adoptive transfer of T cells.

DOI: https://doi.org/10.1038/s41577-025-01223-9