bims-tuinly 2025-08-10 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–08–10
24 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

A pan-cancer comparative analysis of the cancer genome atlas transcriptomic TIL-immune signatures.
Prognostic significance of PARPBP expression and CD8+ tumor-infiltrating lymphocytes in hepatocellular carcinoma.
CRISPR/Cas9-mediated PD-1 attenuation enhances tumor infiltrating lymphocyte-based adoptive cellular therapy in humanized-PDX model of hepatocellular carcinoma.
Tumour-infiltrating lymphocyte therapy landscape: prospects and challenges.
Generation of TIL-based Cellular Products for Cancer Immunotherapy: Current Insights and the Challenges.
Prognostic Value of Tumor-Infiltrating Lymphocytes in Breast Cancer Patients Treated With Radiotherapy: A Systematic Review of Literature.
Systematic identification of lincRNA-derived immunogenic peptides in melanoma.
Properties of CD8 T-cell-recognized neoantigens in different tumor types.
Role of Multiparametric Ultrasound in Determining the Presence of Tumor-Infiltrating Lymphocytes in Invasive Breast Cancer Insights From B-Mode, SWE, and SMI Modalities: Insights From B-Mode, SWE, and SMI Modalities.
HERV-derived epitopes represent new targets for T-cell-based immunotherapies in ovarian cancer.
Resident Memory T Cell in Metastatic Lymph Nodes Is Associated With Favorable Prognosis in Gastric Cancer Patients.
Systematic screening for functional exon-skipping isoforms using the CRISPR-RfxCas13d system.
Immune-related adverse events associated with cancer immunotherapy.
Role of T cell exhaustion and tissue-resident memory T cells in the expression and prognosis of colorectal cancer.
CD4+ T cell dysfunction in cancer.
Pygo2+ T cells possess immunosuppressive features and inferior immunotherapeutic response in gastric cancer.
Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.
Surprising role of CMV in shaping outcomes of immunotherapy for melanoma - chronic infection yields favourable survival.
Memory T Cells, Recombinant Listeria monocytogenes, and Cancer Vaccines.
CD45 sequestration lowers the signaling threshold in lymphocytes and enhances anti-tumor immunity.
Publisher Correction: Personalized, autologous neoantigen-specific T cell therapy in metastatic melanoma: a phase 1 trial.
Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.
T-cell receptor/CD28-targeted immunotherapeutics selectively drive naive T-cell expansion to generate functional HIV-specific responses.
Ex vivo-generated lymphoid progenitors encompass both T cell and innate lymphoid cell fates.

Cancer Immunol Immunother. 2025 Aug 07. 74(9): 286

A pan-cancer comparative analysis of the cancer genome atlas transcriptomic TIL-immune signatures.

Kyle J Hitscherich, Darryl Nousome, Aaron J Dinerman, Victoria Dulemba, Frank J Lowery, Naris Nilubol.

  Efforts to understand the tumor microenvironment through basic science research and the cancer genome atlas (TCGA) data analysis have led to the creation of unique immune transcriptomic signatures from tumor-infiltrating lymphocytes (TIL). However, no pan-cancer analysis has been conducted to compare the prognostic performance of these signatures using overall survival (OS) or progression-free interval (PFI) as endpoints. We compiled a library of 146 TIL-immune signatures and evaluated gene signature score correlation with OS and PFI for 9,961 available TCGA samples across 33 tumor types. Zhang CD8 TCS demonstrated higher accuracy in prognosticating both OS and PFI across the pan-cancer landscape; however, variability was seen across cancer types and germ cell origin. Cluster analysis compiled a group of six signatures (Oh.Cd8.MAIT, Grog.8KLRB1, Oh.TIL_CD4.GZMK, Grog.CD4.TCF7, Oh.CD8.RPL, Grog.CD4.RPL32) whose association with OS and PFI could potentially be conserved across multiple neoplasms.

Keywords:  Cancer; Immunotherapy; Single cell sequencing; Tumor microenvironment; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s00262-025-04102-3
Lab Invest. 2025 Aug 06. pii: S0023-6837(25)00136-9. [Epub ahead of print] 104226

Prognostic significance of PARPBP expression and CD8+ tumor-infiltrating lymphocytes in hepatocellular carcinoma.

Masako Okada, Misako Sato-Matsubara, Masaru Enomoto, Huu Hoang Truong, Sawako Uchida-Kobayashi, Akihiro Tamori, Tsutomu Matsubara, Kenichi Kohashi, Takeaki Ishizawa, Norifumi Kawada.

  The role of poly (ADP-ribose) polymerase 1 binding protein (PARPBP) in hepatocellular carcinoma (HCC) prognosis remains unclear. This study investigated PARPBP expression in HCC clinical samples and evaluated its clinicopathological significance in relation to CD8-positive tumor-infiltrating lymphocytes (CD8+ TILs). PARPBP expression and CD8+ TIL density were assessed in surgical specimens from 96 patients with HCC. We performed immunohistochemical analysis to determine PARPBP protein levels, which were correlated with clinicopathological features and patient outcomes. Additionally, we performed experiments using a doxycycline-inducible short hairpin RNA system targeting PARPBP in Huh7 cells. Results indicated that moderately and poorly differentiated HCC had significantly higher PARPBP expression than well-differentiated tumors. Patients with high PARPBP expression exhibited shorter recurrence-free survival (RFS) and overall survival (OS) than those with low expression (both P < 0.001). Multivariate analysis showed that high PARPBP expression (hazard ratio [HR], 2.806; P = 0.002), high CD8+ TIL density (HR, 0.148; P < 0.001), and α-fetoprotein ≥ 10 ng/ml (HR, 1.904; P = 0.047) were independent predictors of prognosis. Combined analysis revealed that patients with high PARPBP expression and low CD8+ TIL density had the worst RFS and OS outcomes (both P < 0.001). In vitro experiments showed that the mRNA expression of PARPBP was higher in liver cancer cell lines than in normal liver cells and that PARPBP knockdown suppressed huh7 cell proliferation. In conclusion, elevated PARPBP expression was associated with poor differentiation and survival in patients with HCC. Furthermore, the combination of high PARPBP expression and low CD8+ TIL density improved prognostic accuracy.

Keywords:  CD8(+) TILs; PARPBP; hepatocellular carcinoma; immunohistochemistry; prognosis

DOI:  https://doi.org/10.1016/j.labinv.2025.104226
Transl Oncol. 2025 Aug 02. pii: S1936-5233(25)00215-3. [Epub ahead of print]60 102484

CRISPR/Cas9-mediated PD-1 attenuation enhances tumor infiltrating lymphocyte-based adoptive cellular therapy in humanized-PDX model of hepatocellular carcinoma.

Wu Ge, Huaping Liu, Di Wu, Yang Hu, Qi Liang, Muqi Liu, Hao Liu, Jianmin Wu, Juan Zhang, Yao Deng, Kedar Ghimire, Pengfei Rong, Wei Wang, Xiaoqian Ma.

   BACKGROUND: Tumor-infiltrating lymphocyte (TIL)-based adoptive cellular therapy (ACT) has become a promising therapeutic approach due to its ability to effectively control disease in multiple types of solid tumor. Antibodies against the negative immune checkpoint programmed cell death protein 1 (PD-1) have been widely used in cancer immunotherapy. We hypothesized that PD-1 depletion in hepatocellular carcinoma (HCC) TIL-derived T cells would enhance their anti-tumor efficacy.
METHODS: CRISPR/ Cas9 system was employed to target PDCD1 in HCC TIL-derived T cells. The phenotypic and functional changes were analyzed by flow cytometry. T-cell receptor (TCR) sequencing and bulk RNA-sequencing of PD-1-edited or non-edited T cells was conducted to examine their differences. Finally, we demonstrated the ability of PD-1-edited or non-edited T cells to inhibit tumor growth in HCC patient-derived xenograft (PDX) models.
RESULTS: CRISPR/Cas9 system was demonstrated to provide an effective and stable PD-1-editing efficiency. The phenotypes, effector and memory subpopulations of the PD-1-edited T cells were found to have maintained stability, while they did acquire higher potential in terms of autologous tumor cell elimination. Compared to their counterpart, PD-1-edited T cells also retained a higher level of homology with the whole and tumor-specific TCR clonotypes of primary HCC TILs. Furthermore, PD-1-edited T cells exhibited a superior anti-tumor response compared with non-edited T cells in HCC PDX models.
CONCLUSION: Taken together, our results have provided a foundation for the clinical application of ACT based on genetically modified TIL, offering a new perspective on exploring clinical immunotherapy strategies for HCC, and potentially other solid tumors.

Keywords:  Adoptive cellular therapy; CRISPR/Cas9; HCC PDX; PD-1; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.tranon.2025.102484
BMJ Oncol. 2025 ;4(1): e000566

Tumour-infiltrating lymphocyte therapy landscape: prospects and challenges.

Ruqin Chen, Jeffrey Johnson, Ali Rezazadeh, Arkadiusz Z Dudek.

  Tumour-infiltrating lymphocyte (TIL) therapy has emerged as a promising adoptive cell transfer strategy for solid tumours. The recent accelerated approval of lifileucel by the Food and Drug Administration marks a significant milestone in the clinical application of TIL therapy. This review comprehensively examines the historical development, biology, clinical efficacy, safety and limitations of TIL therapy. We explore advancements in TIL manufacturing, including novel culture techniques, genetic modifications and automation, to enhance scalability and effectiveness. Despite promising results, TIL therapy faces challenges such as high-dose interleukin-2 toxicity, complex manufacturing processes and immune evasion mechanisms. Emerging strategies, including checkpoint inhibitor combinations, engineered TIL constructs and metabolic reprogramming, aim to improve TIL therapeutic efficacy. This review provides insights into the evolving landscape of TIL therapy and its potential to enhance current cancer immunotherapy.

Keywords:  Cell engineering; Cell therapy; Immunotherapy; Melanoma; Solid tumour

DOI:  https://doi.org/10.1136/bmjonc-2024-000566
Acta Naturae. 2025 Apr-Jun;17(2):17(2): 15-27

Generation of TIL-based Cellular Products for Cancer Immunotherapy: Current Insights and the Challenges.

D V Kuznetsova, T V Petrova.

  Tumor-infiltrating T lymphocytes (TILs) are a population of T cells present in tumor tissue and enriched in tumor antigen-specific clones. TILs participate in the adaptive antitumor immune response, which makes them a promising candidate for cancer immunotherapy. The concept framing this type of therapy involves the extraction of T cells from a patient's tumor, followed by their in vitro expansion and reinfusion into the same patient in large quantities. This approach enhances the antitumor immune response and allows one to affect cancer cells resistant to other types of treatment. In 2024, the first TIL-based drug was approved for melanoma treatment. The possibility of using TILs for treating other solid tumors is currently being considered, and novel methods aiming to increase the efficiency of generating TIL cultures from tumor tissues in vitro are being developed. However, despite the significant progress achieved in this area, there remain unresolved issues and problems, including the lack of standardized protocols for obtaining, expanding, and cryopreserving TILs, the complexity related to their isolation and the duration of that, as well as insufficient efficiency. Our review focuses on the concept of immunotherapy using TILs, the main stages involved in generating a TIL-based cellular product, associated problems, and further steps in the production of TIL cultures that aim to improve efficiency as relates to production and ensure a wider application of the therapy.

Keywords:  T-cell therapy; TIL; immunotherapy; tumor-infiltrating T lymphocytes

DOI:  https://doi.org/10.32607/actanaturae.27559
Clin Breast Cancer. 2025 Jul 17. pii: S1526-8209(25)00200-9. [Epub ahead of print]

Prognostic Value of Tumor-Infiltrating Lymphocytes in Breast Cancer Patients Treated With Radiotherapy: A Systematic Review of Literature.

Yasmin A Civil, Nora D Purcell, Ralph de Vries, Arlene L Oei, Victor L J L Thijssen, Tanja D de Gruijl, Berend J Slotman, Famke L Schneiders, H J G Desirée van den Bongard.

  High tumor-infiltrating lymphocytes (TILs) levels in triple-negative and HER2-positive breast cancer are associated with better survival outcomes, highlighting its potential as prognostic biomarkers. Radiotherapy can also trigger immune cell infiltration. This systematic review evaluates the prognostic value of TILs in radiotherapy-treated breast cancer patients. A literature search (in PubMed, Embase and Web of Science) was performed up to April 5, 2024 (PROSPERO registration CRD42024401741). Two independent reviewers screened articles according to predefined criteria, resolving discrepancies through consensus. The collected outcomes were prognostic value of TILs for ipsilateral breast tumor recurrence (IBTR), any recurrence, distant metastasis (DM), overall survival (OS) and disease-free survival (DFS). Of 10,927 records, 11 studies (3899 patients) were included. Patients underwent lumpectomy or mastectomy, with or without postoperative radiotherapy. Three studies examined neoadjuvant partial breast irradiation. The stroma threshold for high vs. low TILs ranged from 5 to 50%, with most patients (73%) having low TILs. Low TILs patients significantly benefited from radiotherapy in reducing IBTR and any recurrence. In luminal B, triple-negative and HER2-positive subtypes, high TILs were associated with better outcomes in DM, OS and DFS. For radiotherapy-treated luminal A breast cancer, low TILs were associated with improved OS. For DCIS patients, low TILs correlated with reduced IBTR. TILs could be a prognostic biomarker for radiotherapy-treated breast cancer patients. However, study heterogeneity complicates comparisons. To refine personalized treatment, further prospective studies are necessary to investigate TILs levels and the impact of neoadjuvant radiotherapy on oncological outcomes across different breast cancer subtypes.

Keywords:  Personalized medicine; Prognostic biomarker; Recurrence; Survival; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.clbc.2025.07.005
Oncoimmunology. 2025 Dec;14(1): 2538684

Systematic identification of lincRNA-derived immunogenic peptides in melanoma.

Emilie Dupré, Amélie Guiho, Tiffany Beauvais, Léna Labous, Tristan Cardon, Corine Bertolotto, Amir Khammari, Gaelle Quéreux, Michel Salzet, Nathalie Labarrière, Catherine Rabu, François Lang.

  The search for reliable shared tumor-specific antigens (TSAs) to improve cancer immunotherapy is on-going. The so-called non-coding regions of the genome have recently been shown to give rise to immunogenic peptides, including the melanoma-specific antigen MELOE-1 which is translated from the long intergenic non-coding RNA (lincRNA) meloe in an IRES-dependent manner. Here, we present a strategy to systematically identify tumor-specific antigens produced by ORFs within lincRNAs with IRES-like upstream structures. We provide evidence suggesting that in the melanocytic lineage a significant proportion of the selected lincRNAs can produce immunogenic peptides. T cell repertoires against some of these peptides were found in peripheral blood mononuclear cells (PBMCs) from healthy donors and melanoma patients, and in tumor-infiltrating lymphocytes (TILs) from metastatic melanoma patients. Finally, CD8+ T cell lines from melanoma patients specific for three of the characterized HLA-A *0201 epitopes could recognize melanoma cell lines, which were enhanced by reticular stress. Thus, these peptides may represent a new class of shared TSAs in melanoma and are attractive candidates for evaluation as targets for immunotherapy in preclinical studies. In addition, our selection strategy has the potential to identify new lincRNA-derived antigens in other cancers.

Keywords:  Cancer immunotherapy, T cell epitopes; long intergenic non-coding RNA; melanoma; tumor antigens

DOI:  https://doi.org/10.1080/2162402X.2025.2538684
Immunooncol Technol. 2025 Sep;27 101062

Properties of CD8 T-cell-recognized neoantigens in different tumor types.

S L C Ketelaars, M M van Buuren, A Gangaev, N van Rooij, S Patiwael, K Hoefakker, L F Fanchi, P Baas, M van der Heijden, M Kok, T N Schumacher, P Kvistborg, J B A G Haanen.

   Background: Neoantigen-based immunotherapies rely on computational tools predicting peptide immunogenicity based on properties such as its expression level, binding affinity to human leukocyte antigen (HLA), likelihood of proteasomal cleavage and dissimilarity from wild-type peptide. However, current datasets are scarce and limited to highly mutated tumor types such as melanoma and lung cancer, leaving uncertainty about the value of these properties in other tumor types.
Materials and methods: To investigate this, we retrospectively analyzed the properties of immunogenic neoantigens identified in CD8 T-cell recognition screens of predicted neoantigens in tumor-infiltrating lymphocytes (TILs) from 12 melanoma patients and peripheral blood mononuclear cells (PBMCs) from 14 patients with mesothelioma, triple-negative breast cancer or urothelial cancer. In both experimental settings, CD8 T-cell recognition was assessed using a combinatorial peptide-HLA (pHLA) multimer-based technology.
Results: CD8 T-cell responses were detected against in total 34 of the 8103 predicted neoantigens (0.4%). In both PBMCs and TILs, the eluted ligand (EL) score-the predicted likelihood of a pHLA being presented on the cell surface-was the strongest predictor of immunogenicity, followed by predicted HLA binding affinity. Moreover, in the TILs, the frequency of neoantigen-specific CD8 T cells was strongly correlated with these properties across the 12 patients.
Conclusions: These findings underscore the value of both EL score and HLA binding affinity as key predictors of neoantigen immunogenicity in different tumor types. Furthermore, we demonstrate for the first time an immunodominance hierarchy of neoantigen-specific CD8 T-cell responses across patients in ex vivo expanded TIL cultures.

Keywords:  CD8 T-cell recognition; HLA binding affinity; eluted ligand score; immunodominance hierarchy; neoantigen immunogenicity; pHLA multimer screen

DOI:  https://doi.org/10.1016/j.iotech.2025.101062
J Ultrasound Med. 2025 Aug 02.

Role of Multiparametric Ultrasound in Determining the Presence of Tumor-Infiltrating Lymphocytes in Invasive Breast Cancer Insights From B-Mode, SWE, and SMI Modalities: Insights From B-Mode, SWE, and SMI Modalities.

Yasemin Kayadibi, Gul Esen, Seda Aladag Kurt, Ceyda Sönmez Wetherilt, Tulin Ozturk, Yasemin Nur Icten, Fusun Taskin.

   OBJECTIVE: To evaluate the relationship between tumor-infiltrating lymphocyte (TIL) levels and multiparametric ultrasonography (US) findings combining B-mode US, shear wave elastography (SWE), and superb microvascular imaging (SMI) in patients with invasive breast cancer, and to explore the potential of sonographic imaging modalities in predicting the tumor immune microenvironment.
METHODS: This retrospective study included 148 patients diagnosed with invasive breast carcinoma between September 2021 and December 2024. Patient age, medical history, and immunohistopathological characteristics (grade, hormone positivity, Ki-67 ratio, subtype) of the lesions were recorded. TIL levels were assessed on hematoxylin-eosin (H&E) stained slides by pathologists following the International TILs Working Group guidelines, and lesions were categorized by different TIL levels (presence/absence, ≥10%, ≥20%, ≥30%). US evaluations were performed using a Toshiba Aplio A system (Canon, Tokyo, Japan) with a 12-16 MHz breast probe. Imaging assessments included B-mode ultrasound (morphology, echogenic halo sign), SWE (E-mean, E-ratio, stiff rim sign), and SMI (Adler classification, SMI vascular index). Associations between TIL levels and imaging parameters were analyzed using Chi-square tests for categorical and Student's t-tests for continuous variables (SWE and SMI).
RESULTS: TIL was detected in 121 of 148 lesions (81.8%). TIL value was >10% in 33 lesions, >20% in 12, and >30% in 8 lesions. On B-mode US, round/oval tumor shape (p = .003 at level of TIL > 20%, p = .001 at level of TIL > 30%) and non-parallel orientation (p = .023) were more prevalent in TIL positive lesions. On SWE, tumors with TIL levels ≥10% were significantly associated with higher E-mean values (130 ± 24.7 vs. 107.9 ± 36, p = .001) and the presence of a stiff rim sign (p < .001). Penetrating vascular structures were more commonly observed on SMI in lesions with TIL ≥ 10% (p = .023), along with a higher mean vascular index (p = .036). No significant difference was found in other US-SWE and SMI findings (all p > .4).
CONCLUSION: Our findings suggest that US features, particularly vascularity on SMI and stiffness on SWE, may reflect TIL presence in breast cancer. However, methodological variations and differing TIL levels across studies may influence inconsistent associations, especially with SWE. Further comprehensive studies are needed to clarify this relationship.

Keywords:  breast cancer; immuno‐oncology; shear wave elastography; superb microvascular imaging; tumor‐infiltrating lymphocytes; ultrasound

DOI:  https://doi.org/10.1002/jum.70022
J Immunother Cancer. 2025 Aug 03. pii: e010099. [Epub ahead of print]13(8):

HERV-derived epitopes represent new targets for T-cell-based immunotherapies in ovarian cancer.

Paola Bonaventura, Audrey Page, Olivier Tabone, Yann Estornes, Virginie Mutez, Marie Delles, Sarah Moran, Clarisse Dubois, Thibault Richard, Marjorie Lacourrège, Marie Michelas, Dina M Tawfik, Ema Etchegaray, Adrian Valente, Rasha E Boulos, Gabriel Jimenez Dominguez, Isabelle Treilleux, Nicolas Chopin, Olivia Le Saux, Nicolas Chuvin, Nicolas Gadot, Maha Ayyoub, Qing Wang, Jenny Valladeau-Guilemond, Stéphane Depil.

   BACKGROUND: Ovarian cancer represents the most lethal gynecological cancer with poor response to checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T-cell epitopes for cancer immunotherapy regardless of the tumor mutational burden.
METHODS: A transcriptomic analysis based on RNA sequencing was developed to quantify the expression of HERV-K sequences containing the selected epitopes. The presence of HERV-K/HML-2 Gag antigen was then assessed by immunohistochemistry (IHC) on tumor microarrays from ovarian cancer samples and normal ovarian tissues. A specific immunopeptidomics approach was developed to detect epitopes on human leukocyte antigens (HLA) molecules. Epitope-specific CD8+ T cells were quantified by multimer staining. HERV-specific T cells were obtained after in vitro stimulation of T cells from HLA-A2-positive healthy donors or patients with ovarian cancer, and in vitro target cell killing was evaluated using real-time analysis. In vivo antitumor efficacy of HERV-specific T cells was assessed in an avian embryo model.
RESULTS: Epitope-containing HERV transcripts were significantly higher in ovarian cancers compared with normal tissues. The presence of the HERV-K/HML-2 Gag antigen was confirmed by IHC in 20/40 (50%) ovarian cancers while no Gag expression was found in normal ovarian tissue samples. Immunopeptidomics analysis revealed the presence of epitopes on HLA molecules on the surface of ovarian tumor cell lines but not on normal primary cells from critical tissues. Low percentages of HERV-specific T cells were detected among tumor-infiltrating lymphocytes from ovarian cancers. Furthermore, in vitro stimulation of patient T cells induced functional epitope-specific T cells, confirming the immunogenicity of these epitopes in patients with ovarian cancer. In vitro, HERV-specific T cells specifically killed ovarian cancer cells in an HLA class I-restricted manner while sparing normal HLA-A2-positive primary cells derived from critical tissues. Epitope-specific CD8+ T cells exhibited a strong antitumoral activity in vivo, inducing a highly significant decrease in tumor volume in comparison with control groups.
CONCLUSION: These results provide the preclinical rationale for developing T-cell-based approaches against HERV-K-derived epitopes in ovarian cancer.

Keywords:  Immunotherapy; Ovarian Cancer; T cell

DOI:  https://doi.org/10.1136/jitc-2024-010099
Cancer Sci. 2025 Aug 03.

Resident Memory T Cell in Metastatic Lymph Nodes Is Associated With Favorable Prognosis in Gastric Cancer Patients.

Masaki Nishiyama, Yuichiro Miki, Hiroaki Tanaka, Seiji Natsuki, Kenji Kuroda, Mami Yoshii, Tatsuro Tamura, Takahiro Toyokawa, Shigeru Lee, Kiyoshi Maeda.

  Infiltration of resident memory T cells (TRMs) in the main tumor has been reported as a favorable prognostic factor. However, the role of TRMs in the lymph nodes (LNs) remains unclear. Thus, we examined the prognostic impact of TRMs infiltration within LNs of patients with gastric cancer (GC). Among 151 patients with metastasis to LN station No. 3, we classified them into two groups (CD103hi and CD103lo) based on the number of CD103+ T cells using immunohistochemical staining and analyzed the association between these groups and survival outcomes. We also examined the phenotype of CD8+ CD103+ T cells in the metastatic LNs using flow cytometry. Among patients with LN metastasis, metastasis to LN station No. 3 was significantly associated with a poor prognosis. There was a significant correlation between the number of CD8+ CD103+ T cells between the main lesion and the metastatic LNs. CD103hi was associated with a favorable prognosis (5-year overall survival [OS], log-rank p = 0.001; 5-year recurrence free survival [RFS], log-rank p = 0.001). Among adjuvant chemotherapy cases, patients with CD103hi exhibited significantly better OS and RFS than those with CD103lo (OS, log-rank p < 0.001; RFS, log-rank p < 0.001). Flow cytometry revealed that PD-1 expression in CD8+ CD103+ T cells was higher in metastatic than in normal LNs. Among patients with CD103hi, those with high PD-1 expression exhibited significantly better OS than those with low PD-1 expression. In conclusion, the infiltration of TRMs into LNs is a critical prognostic factor in GC.

Keywords:  CD103; gastric cancer; lymph node metastasis; resident memory T cell; survival outcome

DOI:  https://doi.org/10.1111/cas.70163
Cell Syst. 2025 Jul 29. pii: S2405-4712(25)00184-X. [Epub ahead of print] 101351

Systematic screening for functional exon-skipping isoforms using the CRISPR-RfxCas13d system.

Qiang Sun, Xuejie Ma, Qianqian Ning, Shuang Li, Ping Wang, Xiangmin Tan, Qian Jin, Junnian Zheng, Yang Li, Dong Dong.

  Exon skipping (ES) is the most prevalent form of alternative splicing and a hallmark of tumorigenesis, yet its functional roles remain underexplored. Here, we present a CRISPR-RfxCas13d-based platform for transcript-specific silencing of ES-derived isoforms using guide RNAs (gRNAs) targeting exon-exon junctions. We designed a transcriptome-wide gRNA library against 3,744 human ES events and conducted loss-of-function screens in colorectal cancer (CRC) cells in vitro and in vivo. This screen uncovered multiple ES events essential for CRC growth, notably HMGN3 Δ6, an isoform arising from exon 6 skipping, which enhanced tumor proliferation. Functional validation confirmed the oncogenic role of HMGN3 Δ6 and its necessity for CRC progression. Our study establishes CRISPR-RfxCas13d as a powerful tool for isoform-specific functional genomics and reveals a widespread, previously uncharacterized layer of tumor biology driven by ES. These findings position ES-derived transcripts as promising targets for therapeutic intervention in cancer.

Keywords:  CRISPR-RfxCas13d screening; HMGN3Δ6; colorectal cancer; exon skipping

DOI:  https://doi.org/10.1016/j.cels.2025.101351
Med. 2025 Jul 28. pii: S2666-6340(25)00227-2. [Epub ahead of print] 100800

Immune-related adverse events associated with cancer immunotherapy.

Smith Kungwankiattichai, Amrita Desai, Shelby Koppinger, Richard T Maziarz.

  Immunotherapy has become central to cancer care, whether in combination with traditional chemotherapy, as adjuvant therapy, or as primary therapy, and has been demonstrated to be central to treatment of newly diagnosed or relapsed disease in multiple randomized control trials. Antibody-based immunotherapy initiated the treatment revolution, but now immune effector cellular therapy is rapidly emerging and expanding its indications. Efficacy determinations have led to multiple international regulatory approvals, but unique significant toxicities have also been identified. It remains critical to understand risk factors that predict for adverse events that are encountered after administration of cancer immunotherapy. Similarly, identification of patient-related factors that enhance or diminish therapeutic efficacy, independent of the underlying malignancy, is critical for balancing the benefit and risk of immunotherapy. This review addresses the multiple new cellular therapy initiatives and addresses the importance of appropriate patient selection that will ultimately maximize the treatment benefit.

Keywords:  allogeneic hematopoietic cell transplantation; bispecific antibodies; checkpoint inhibitors; chimeric antigen receptor T cells; cytokine release syndrome; natural killer cells; neurotoxicity; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.medj.2025.100800
Sci Rep. 2025 Aug 05. 15(1): 28503

Role of T cell exhaustion and tissue-resident memory T cells in the expression and prognosis of colorectal cancer.

Han Wu, Pei-Wen Fan, Ya-Ning Feng, Cheng Chang, Ting Gui, Jia-Bei Meng, Ruo-Zheng Wang.

  The tumour microenvironment (TME) is complex and dynamic, and changes significantly with tumour progression. Studying the evolving state of T cells, especially tumour-specific subsets, has become feasible. However, the roles of exhausted T cells (Tex) and pre-exhausted tissue-resident memory T cells (pf-Trm), which emerge after prolonged antigen stimulation, remain unclear. Using single-cell sequencing data, we analyzed the immune landscape of patients with colorectal cancer (CRC) across clinical stages to quantify the abundance of T cell subtypes. Functional enrichment analysis revealed that early stage Tex cells retained some functionality, whereas advanced stage Tex cells showed a significant functional loss. Early stage pf-Trm cells actively participate in immune surveillance and antigen presentation, whereas advanced stage pf-Trm cells exhibit reduced functions. Flow cytometry analysis of clinical cohorts was used to measure the proportions of Tex and pf-Trm. Elevated levels of PD-1 and Tim-3 have been detected in TILs from CRC patients. Data from The Cancer Genome Atlas (TCGA) linked high Tex levels to poor prognosis in CRC, while pf-Trm correlated with better outcomes in early CRC but worse outcomes in advanced CRC due to functional exhaustion. Thus, Tex and pf-Trm cells may serve as prognostic biomarkers, and Tim-3 and CD103 may be promising targets for immune checkpoint inhibitors.

Keywords:  Clinical prognosis; Colorectal cancer; Pre-failure tissue-resident memory T cells; T-cell exhaustion; Tumour microenvironment

DOI:  https://doi.org/10.1038/s41598-025-14409-x
J Exp Med. 2025 Sep 01. pii: e20241417. [Epub ahead of print]222(9):

CD4+ T cell dysfunction in cancer.

Hrishi Venkatesh, Lawrence Fong.

While the importance of CD8+ T cells in successful cancer immunotherapy is well-established, CD4+ T cells are increasingly recognized as key mediators of effective anti-tumor immunity. However, the mechanisms underlying the functional impairment of CD4+ T cells in tumors are not as well characterized as in CD8+ T cells. In this review, we will explore how CD4+ T cells are altered in tumor-bearing hosts, compare these changes to those observed in CD8+ T cells, and discuss how these changes impact tumor control. Approaches that counteract functional impairment in tumor-reactive CD4+ T cells may further enhance the efficacy of cancer immunotherapy.

DOI: https://doi.org/10.1084/jem.20241417
Front Immunol. 2025 ;16 1596434

Pygo2+ T cells possess immunosuppressive features and inferior immunotherapeutic response in gastric cancer.

Weilong Chang, Huifang Yan, Yawei Zhang, Zibo Sang, Bei Bu, Rui Deng, Kaibo Li, Jiajing Li, Yang Fu, Jinyuan Cui.

   Background: Gastric cancer (GC) poses a significant threat to human health. Despite considerable advancements in immunotherapy for GC, the effectiveness of current immunotherapeutic targets remains constrained by the heterogeneity of the tumor microenvironment and mechanisms of immune evasion. Consequently, the identification of novel immunotherapy targets has emerged as a critical area of research. This study investigates the potential of Pygo2 as a target for immunotherapy in GC.
Methods: The expression and cell localization of Pygo2 in GC tissues were characterized by single cell sequencing, flow cytometry and mIHC. The relationship among Pygo2 expression and prognosis, immune microenvironment and immunotherapy effect was studied in 282 gastric cancer patients.
Results: The findings indicate a significant upregulation of Pygo2 expression in GC tissues, particularly within tumor cells and T cells. Pygo2 expression in T cells is not only correlated with the advanced T stage and N stage but also inversely associated with patient survival. Additionally, overexpression of T cell Pygo2 resulted in a significant increase in TCF7, which suggested Pygo2+ T cells might represent a subset of exhausted T cells. The study also demonstrated that the density of Pygo2+ CD8+ T cells is negatively correlated with the efficacy of immunotherapy.
Conclusion: Tumor-infiltrating Pygo2+ T cells could be applied as a clinical prognosticator and a predictive biomarker for immunotherapy responsiveness to GC. These findings offer new therapeutic targets for the treatment of GC and provide fresh insights into cancer treatment strategies.

Keywords:  Pygo2; gastric cancer; immune microenvironment; immunotherapeutic response; single-cell sequencing

DOI:  https://doi.org/10.3389/fimmu.2025.1596434
bioRxiv. 2025 Jul 28. pii: 2025.07.24.665398. [Epub ahead of print]

Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.

Tyler R Colson, James J Cameron, Hayley I Muendlein, Mei-An Nolan, Jamie L Leiriao, James H Kim, Alexander N Poltorak, Xudong Li.

Reprogramming autoreactive CD4 + effector T (T eff ) cells into immunosuppressive regulatory T (T reg ) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed T regs under inflammatory conditions remain unclear. Here, we show that demethylation of core T reg identity genes in T eff cells yields lineage-stable Effector T cell Reprogrammed T regs (ER-T regs ). A single adoptive transfer of ER-T regs not only prevents autoimmune neuroinflammation in mice when given before disease onset but also arrests its progression when administered after onset. Compared to Foxp3-overexpressing T eff cells, induced T regs from naïve precursors, and endogenous T regs , ER-T regs provide superior protection against autoimmune neuroinflammation. This enhanced efficacy stems from their inherited autoantigen specificity and selectively preserved effector-cell transcriptional programs, which together bolster their fitness in inflammatory environments and enhance their suppressive capacity. Our results establish epigenetic reprogramming of autoreactive T eff cells as an effective approach to generate potent, stable T regs for the treatment of refractory autoimmune conditions.

DOI: https://doi.org/10.1101/2025.07.24.665398
Nat Rev Clin Oncol. 2025 Aug 05.

Surprising role of CMV in shaping outcomes of immunotherapy for melanoma - chronic infection yields favourable survival.

Anthony R Cillo, John M Kirkwood.

DOI: https://doi.org/10.1038/s41571-025-01065-3
Front Biosci (Landmark Ed). 2025 Jul 31. 30(7): 36329

Memory T Cells, Recombinant Listeria monocytogenes, and Cancer Vaccines.

Abolaji Samson Olagunju, Maribel Limachi Loza, Marielly Câmara Rocha, Gustavo P Amarante-Mendes.

  Memory T cells are essential for effective and durable immune responses, as they provide long-term immunological surveillance and rapid reactivity upon re-exposure to a given pathogen or cancer cell. In solid tumors, the immunosuppressive tumor microenvironment (TME) often hinders immune activation, making enhancing memory T cell formation and persistence a key goal in cancer immunotherapy. Novel strategies are exploring ways to support these memory T cells, including using Listeria monocytogenes as a cancer vaccine vector. Notably, L. monocytogenes has unique properties that make it an ideal candidate for this purpose: it is highly effective at activating T cells, promoting the differentiation and survival of memory T cells, and modulating the TME to favor immune cell function. Thus, by leveraging the ability of L. monocytogenes to induce a strong, sustained T-cell response, researchers aim to develop vaccines that provide lasting immunity against tumors, reduce recurrence rates, and improve patient survival outcomes. This mini-review highlights the potential of memory T cell-focused cancer immunotherapy and the promising role of L. monocytogenes in advancing these efforts.

Keywords:  CD8+ T lymphocytes; Listeria monocytogenes; cancer vaccines; memory T cells

DOI:  https://doi.org/10.31083/FBL36329
bioRxiv. 2025 Aug 01. pii: 2025.07.29.667400. [Epub ahead of print]

CD45 sequestration lowers the signaling threshold in lymphocytes and enhances anti-tumor immunity.

Lauren Duhamel, Yiming J Zhang, William Pinney, Elizabeth Fink, Qingyang Henry Zhao, Anna Romanov, Jordan A Stinson, Luciano Santollani, Joseph R Palmeri, Owen T Porth, Darrell J Irvine, K Dane Wittrup.

CD45 plays a central role in immune signal regulation by controlling the spatial dynamics of phosphatase activity through steric segregation of its bulky rigid extracellular domain. To modulate CD45 activity, here we develop and characterize protein engineering approaches to induce multivalent clustering of CD45, effectively mimicking the endogenous local receptor sequestration during immune synapse formation. In doing so, we engineer a biologic that enables precise, tunable control over CD45 surface localization and activity. CD45 sequestration exhibited striking synergy when administered in combination with intratumorally anchored IL-12 therapy, markedly delaying tumor progression and extending survival in syngeneic murine melanoma and carcinoma models. Immune profiling revealed that CD8⁺ T cells are essential mediators of this synergistic antitumor response. Mechanistically, IL-12 initiates a wave of antigen generation and T cell priming, while CD45 sequestration subsequently enhances tumor-specific CD8⁺ T cell activation, expansion, and functional states within the tumor-draining lymph node. These findings suggest that CD45 sequestration lowers the activation threshold of T cells, broadens the tumor-reactive T cell repertoire, and therefore promotes more robust tumor-specific T cell responses. Altogether, we establish CD45 as a promising novel target for cancer immunotherapy, capable of potentiating strong anticancer immune responses.

DOI: https://doi.org/10.1101/2025.07.29.667400
Nat Med. 2025 Aug 04.

Publisher Correction: Personalized, autologous neoantigen-specific T cell therapy in metastatic melanoma: a phase 1 trial.

Jessica S W Borgers, Divya Lenkala, Victoria Kohler, Emily K Jackson, Matthijs D Linssen, Sebastian Hymson, Brian McCarthy, Elizabeth O'Reilly Cosgrove, Kristen N Balogh, Ekaterina Esaulova, Kimberly Starr, Yvonne Ware, Sebastian Klobuch, Tracey Sciuto, Xi Chen, Gauri Mahimkar, Joong Hyuk F Sheen, Suchitra Ramesh, Sofie Wilgenhof, Johannes V van Thienen, Karina C Scheiner, Inge Jedema, Michael Rooney, Jesse Z Dong, John R Srouji, Vikram R Juneja, Christina M Arieta, Bastiaan Nuijen, Claudia Gottstein, Olivia C Finney, Kelledy Manson, Cynthia M Nijenhuis, Richard B Gaynor, Mark DeMario, John B Haanen, Marit M van Buuren.

DOI: https://doi.org/10.1038/s41591-025-03896-0
JCI Insight. 2025 Jul 31. pii: e185581. [Epub ahead of print]

Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.

Tyler R Colson, James J Cameron, Hayley I Muendlein, Mei-An Nolan, Jamie L Leiriao, James H Kim, Alexander N Poltorak, Xudong Li.

  Reprogramming autoreactive CD4⁺ effector T (Teff) cells into immunosuppressive regulatory T (Treg) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed Tregs under inflammatory conditions remain unclear. Here, we show that epigenetic activation of core Treg identity genes in Teff cells yields lineage-stable Effector T cell Reprogrammed Tregs (ER-Tregs). A single adoptive transfer of ER-Tregs not only prevents autoimmune neuroinflammation in mice when given before disease onset but also arrests its progression when administered after onset. Compared to Foxp3 overexpressing Teff cells, induced Tregs from naïve precursors, and endogenous Tregs, ER Tregs provide superior protection against autoimmune neuroinflammation. This enhanced efficacy stems from their inherited autoantigen specificity and selectively preserved effector cell transcriptional programs, which together bolster their fitness in inflammatory environments and enhance their suppressive capacity. Our results establish epigenetic reprogramming of autoreactive Teff cells as an effective approach to generate potent, stable Tregs for the treatment of refractory autoimmune conditions.

Keywords:  Autoimmune diseases; Autoimmunity; Epigenetics; Immunology; Inflammation; T cells

DOI:  https://doi.org/10.1172/jci.insight.185581
J Virol. 2025 Aug 05. e0018825

T-cell receptor/CD28-targeted immunotherapeutics selectively drive naive T-cell expansion to generate functional HIV-specific responses.

April L Mueller, Sara Lamcaj, Scott Garforth, Christopher Hiner, Darien Woodley, Kitt Paraiso, Tian Mi, Simon Low, Ben Youngblood, Steven C Almo, Harris Goldstein.

  Adoptive cell transfer (ACT), a promising immunotherapeutic approach, treats viral infections or cancer by ex vivo expansion and infusion of antigen-specific CD8+ T cells, respectively. However, its wider use is limited by logistical challenges associated with the conventional method of using patient-derived dendritic cells (DCs) loaded with peptides for ex vivo antigen-specific CD8+ T cell expansion. To overcome these limitations, we developed Immuno-STAT (IST), a dimeric protein scaffold that delivers peptide-specific T cell receptor (TCR) activation with or without CD28 costimulatory signals to expand CD8+ T cells specific for defined viral or cancer epitopes. In this proof-of-concept study, we demonstrate that anti-CD28-IST can selectively activate and expand polyfunctional cytotoxic CD8+ T cells from the naive repertoire, targeting the HIV-associated SL9 or melanoma-associated MART-1 epitopes. Naive MART-1-specific CD8+ T cells were reliably expanded by both peptide-loaded DCs and IST. In contrast, naive SL9-specific CD8+ T cells were expanded only by SL9-specific IST and not by conventional DC-based approaches, underscoring a unique ability of IST to stimulate some naive HIV-specific T cell responses. IST-derived SL9-specific CD8+ T cells exhibited potent cytotoxicity, diverse TCR clonotypes, and memory-differentiated phenotypes, marking a significant advance in generating antigen-specific T cells against HIV. The modular IST platform provides a scalable modality to stimulate naive CD8+ T cells to potentially mobilize preemptive CD8+ T cell responses against predicted immune escape variants, as well as subdominant conserved HIV epitopes to empower the development of innovative ACT, vaccine, and other immune strategies to advance treatments for HIV, other persistent viral infections, and cancer.
IMPORTANCE: Adoptive transfer of ex vivo-expanded T cells with potent and broad anti-HIV activity may control HIV replication in people with HIV in the absence of antiretroviral therapy. To selectively activate and expand naive CD8+ cells targeting defined viral or cancer epitopes, we developed a unique protein architecture, termed Immuno-STAT, which delivers cognate peptide-specific T cell receptor (TCR) activation alone or in combination with CD28 costimulation. We demonstrated that polyfunctional cytotoxic CD8+ T cells specific for the HIV-associated SL9 or melanoma-associated MART-1 epitopes were expanded by αCD28-Immuno-STAT delivering peptide-specific TCR and CD28 signals, but not peptide-specific TCR signals alone. αCD28-Immuno-STAT-generated SL9-specific CD8+ T cells exhibited diverse TCR clonotypes, polyfunctionality, and potent SL9-specific cytotoxicity. Adoptive transfer of αCD28-Immuno-STAT-generated CD8+ T cells specific for defined HIV epitopes may provide the broad yet targeted responses specific for conserved HIV epitopes and predicted immune escape variants required to control HIV replication and provide a functional HIV cure.

Keywords:  HIV; T cells; immunology

DOI:  https://doi.org/10.1128/jvi.00188-25
Front Immunol. 2025 ;16 1617707

Ex vivo-generated lymphoid progenitors encompass both T cell and innate lymphoid cell fates.

Pierre Gaudeaux, Juliette Paillet, Monah Abou Alezz, Ranjita Devi Moirangthem, Sara Cascione, Marta Martin Corredera, Anne-Catherine Dolens, Katrien De Mulder, Imke Velghe, Bart Vandekerckhove, Marieke Lavaert, Noémie Robil, Aurélien Corneau, Hanem Sadek, Pauline Rault, Akshay Joshi, Pierre de la Grange, Frank J T Staal, Tom Taghon, Olivier Negre, Andrea Ditadi, Isabelle André, Tayebeh-Shabi Soheili.

   Introduction: We previously established a feeder-free cell therapy platform for the ex vivo generation of lymphoid-primed progenitors using immobilized Delta-like ligand 4 (DLL4). In vivo studies demonstrated that adoptive transfer of these progenitors accelerates T cell reconstitution following thymic engraftment.
Method: To further explore the full therapeutic potential of this cell product, we performed a comprehensive molecular and phenotypic characterization using single cell RNA sequencing and mass cytometry analysis.
Results: Our analysis revealed the presence of distinct cell subsets within the cellular product characterized mainly by commitment to lymphoid lineages. Using integrated transcriptomic analyses to compare these ex vivo-generated progenitors to in vivo human thymocytes, we revealed strong similarities with early stages of T cell development, underscoring the physiological relevance of our system. We also delineated two distinct developmental trajectories within the CD7+ progenitor population: a T cell-oriented path, marked by CD5 upregulation, and an innate lymphoid cell (ILC)-oriented branch, identified by CD161 expression and an ILC-like gene signature. Despite these lineage predispositions, both subsets demonstrated plasticity, retaining the ability to differentiate into both T cells and natural killer (NK) cells in vitro. Additionally, in our experimental setting, we observed that BCL11B, a transcription factor essential for T cell commitment, regulates negatively myeloid cell differentiation while preserving the potential for NK cell development.
Conclusion: These findings underscore the versatility of DLL4-based lymphoid progenitors in generating either T cells or ILCs in response to environmental cues. This research paves the way for innovative cell therapy approaches to treat immune deficiencies and cancer- and age-related immune dysfunctions.

Keywords:  T cell progenitors; ex vivo differentiation; hematopoietic stem cell; lymphoid cell development; scRNAseq

DOI:  https://doi.org/10.3389/fimmu.2025.1617707