bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2026–04–05
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Autophagy meets tissue-resident memory: Emerging crosstalk and therapeutic opportunities in cutaneous melanoma.
  2. Prognostic value of tumor-infiltrating lymphocytes in colon cancer.
  3. A study exploring the roles of desmoplastic reaction, tumor budding, tumor infiltrating lymphocytes, and depth of invasion as potential predictive parameters for extranodal extension in oral squamous cell carcinoma.
  4. An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.
  5. Prognostic Role of Absolute Monocyte Count, CD163⁺ Macrophages, and CD8⁺ Lymphocytes in Diffuse Large B-Cell Lymphoma Treated with R-CHOP.
  6. Gut microbiota-associated nutritional-immune status predicts prognosis in postoperative NSCLC patients.
  7. T-Cell Receptor Engineered T-Cell Therapy: A Rapidly Evolving Treatment Paradigm for Solid Tumors.
  8. Epigenetic remodeling in sarcoma promotes T-cell infiltration via modulation of the Hippo pathway.
  9. The CD4+ T cell population partners with Tpex CD8+ T cells to mediate antitumor immunity in the tumor microenvironment.
  10. CXCL12-mediated T cell infiltration drives breast cancer metastasis.
  11. Preclinical efficacy of combination therapy with allogeneic induced pluripotent stem cell-derived invariant natural killer T and α-galactosylceramide-pulsed antigen-presenting cells.
  12. Regulatory T cell-derived TGF-β signaling governs the differentiation and maintenance of tumor-infiltrating bystander CD8+ T cells.
  13. Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models.
  14. Unique pattern of endometrial invasion in gastric-type adenocarcinoma of the uterine cervix: a report of two cases.
  15. Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling.
  16. Safety and Feasibility of Infusing Ex Vivo Expanded Allogeneic Canine Natural Killer Cells for the Treatment of Metastatic Solid Tumors.
  17. Unveiling the molecular architecture of T cells and immune synapses with cryo-expansion microscopy.
  18. Brief Report: Low Delta-like Ligand 3 expression and T Cell Exhaustion Drive Resistance to Tarlatamab combined with anti-PD-1 in Small-Cell Lung Cancer.
  19. Activity of Didesmethylrocaglamide in High Grade Serous Ovarian Cancer Using Preclinical In Vitro and In Vivo Models.
  1. Biochim Biophys Acta Rev Cancer. 2026 Mar 30. pii: S0304-419X(26)00052-1. [Epub ahead of print] 189580
    Autophagy meets tissue-resident memory: Emerging crosstalk and therapeutic opportunities in cutaneous melanoma.
    Bogdan Toma, Mariana Pavel-Tanasa, Mihai Danciu.
      Melanoma is a highly immunogenic human cancer characterized by complex immune responses within the tumor microenvironment (TME). Among these, tumor-infiltrating lymphocytes (TILs) and tissue-resident memory T cells (TRM) are strongly associated with favorable prognosis and response to immune checkpoint blockade, reflecting their central role in sustaining anti-tumor immunity. Emerging evidence suggests that the activity and persistence of these T cell subsets are critically influenced by autophagy, a cellular process that maintains metabolic fitness, prevents exhaustion, and supports effector functions under nutrient-limited and stressful conditions typical of the TME. Understanding the autophagy-T cell axis may open new avenues for therapeutic strategies aimed at enhancing melanoma immunosurveillance and improving patient outcomes. In this review, we explore the intersection between TRM-cell biology and autophagy in cutaneous melanoma, outlining TRM differentiation and functions in the tumor setting, reviewing autophagy within melanoma cells, and examining evidence for their potential crosstalk. We further discuss how autophagy may shape TRM development, maintenance, and function, while tumor-intrinsic autophagy modulates TIL and TRM-mediated responses, and conclude by highlighting therapeutic opportunities, including those under investigation in registered clinical trials. By providing insights into this intricate interplay, the review aims to stimulate further investigation and support the development of targeted TRM-based therapeutic strategies for melanoma.
    Keywords:  Autophagy; Clinical trials; Melanoma; Tissue-resident memory T cells; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189580
  2. Indian J Pathol Microbiol. 2026 Jan 01. 69(1): 10-15
    Prognostic value of tumor-infiltrating lymphocytes in colon cancer.
    Bacha Dhouha, Khessairi Neyssem, Kammoun Neirouz, Siala Hager, Lahmar Ahlem, Gharbi Lassad, Ben Slama Sana.
       BACKGROUND: Several clinico-pathological prognostic factors are essential to guide therapeutic management for colon cancer (CC). The benefit of adjuvant chemotherapy remains controversial for patients with stage II CC and is currently not systematically applied. This leads to define two subgroups of patients, "low" and "high risk" of recurrence. In this setting, tumor-infiltrating lymphocytes (TILs) may represent a promising marker.
    AIMS: Our study aimed to assess the prognostic value of TILs in stage II CC.
    MATERIALS AND METHODS: We conducted a retrospective study involving the patients who underwent curative surgery for primary stage II colonic adenocarcinoma. The data were collected over a period of 15 years.
    RESULTS: Seventy patients were included. The mean age of the patients was 60 years. The most frequent circumstances of discovery were abdominal pain (48%), followed by digestive transit disorders (26%) and digestive bleeding (20%). All patients at "high risk" of recurrence had received adjuvant chemotherapy except for seven patients. The mean overall survival and recurrence-free survival rates were 51 and 56 months, respectively. TILs rate varied between 3% and 80% with a median of 50%. TIL rates < 50% significantly decreased recurrence-free survival in univariate analysis (P = 0.001). In multivariate analysis, it was identified as an independent factor for the recurrence-free survival. We found a correlation between the rate of TILs < 50% and the lymphatic invasion (P = 0.022), the high grade of the tumor (P = 0.02) and the tumor size >3 cm (P = 0.009).
    CONCLUSION: TILs represent an important prognostic and predictive factor for stage II CC. It should be introduced in clinical practice to identify patients with "high-risk" stage II CC.
    Keywords:  Adenocarcinoma; colon cancer; infiltrating lymphocytes
    DOI:  https://doi.org/10.4103/ijpm.ijpm_710_24
  3. J Cancer Res Ther. 2026 Jan 01. 22(1): 104-108
    A study exploring the roles of desmoplastic reaction, tumor budding, tumor infiltrating lymphocytes, and depth of invasion as potential predictive parameters for extranodal extension in oral squamous cell carcinoma.
    Trupti R Jansari, Jay Jansari, Vishwa Gevariya, Amit Chauhan, Shikha Shah.
       BACKGROUND: Head and neck squamous cell carcinomas constitute the eighth most common malignancy worldwide. Desmoplastic reaction (DR), tumor budding (TB), tumor-infiltrating lymphocytes (TILs), and depth of invasion (DOI) are some of the histological predictors of extranodal extension (ENE) and poor prognosis. In this study, we aimed to investigate their association in oral squamous cell carcinoma (OSCC).
    MATERIALS AND METHODS: This retrospective analytical study included 329 specimens of OSCC from our hospital. All data were collected from the histopathological records (e.g. age, gender, diagnosis, lymph node metastasis, ENE, DR, TB, TILs, and DOI). The datasets were analyzed using the Chi-square test and GraphPad InStat 3 software.
    RESULTS: The majority of cases were seen in the age group of ≥60 years (221/329, 67.17%). Out of 35 ENE-positive patients, 31 (88.6%) had progressive OSCC. We found a significant association between immature DR (DR-I), high TB (TB-H), and low TILs with pathological DOI (pDOI) >10 mm (P value: <0.0001, 0.001, and < 0.001, respectively). There was a significant association between DR, TB, and TILs at the primary site with that of the ENE sites (P value: 0.02, 0.002, and 0.001, respectively). TB-H and pDOI >10 mm were the independent variables for the prediction of ENE (95% confidence interval [CI] = 1.07-4.95, P value: 0.003 and 95% CI = 1.11-1.52, P value: 0.0008, respectively). TB-H and pDOI >10 mm showed the highest sensitivity (85.1% and 97.1%, respectively) and DR-I exhibited the highest specificity (83.8%) for the presence of ENE.
    CONCLUSION: Detecting ENE not only predicts outcomes but also influences the treatment strategies and quality of life.
    Keywords:  Desmoplastic reaction; extranodal extension; tumor budding; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.4103/jcrt.jcrt_986_25
  4. Front Bioinform. 2026 ;6 1764743
    An integrated automated deep learning framework for annotating tumor-infiltrating lymphocytes in lung adenocarcinoma pathology.
    Xia Li, Kang-Lai Wei, Zhao-Quan Huang, Zi-Yan Huang.
       Objective: Quantitative analysis of tumor-infiltrating lymphocytes (TILs) is crucial in computational pathology studies of lung adenocarcinoma. However, acquiring large-scale, fully annotated datasets remains a major obstacle for the supervised learning approaches that currently dominate high-precision modeling. To address this data bottleneck, we developed a fully automated pipeline for the precise annotation of tissue contours, tumor parenchyma, and lymphocytes in whole-slide images (WSIs).
    Methods: This study utilized WSI data from The Cancer Genome Atlas (TCGA) cohort, with comprehensive manual annotations performed by two pathologists using QuPath software, with all annotations subsequently reviewed by a third senior pathologist. The resulting training dataset comprised over 20,000 annotated units. These annotated data were used to train three core modules consisting of an OpenCV-based image processing pipeline for tissue contour detection, a lightweight U2-NetP model for tumor parenchyma segmentation, and a YOLOv7 object detection framework for TILs identification within stromal regions. The pipeline was rigorously validated on both an independent internal cohort and an external hospital cohort, and its outputs were benchmarked against semi-quantitative assessments from expert pathologists.
    Results: The pipeline demonstrated robust and generalizable performance. For tissue contour detection, the OpenCV-based pipeline achieved a Dice coefficient of 90.90% on the test set. For the core learning-based tasks, the tumor parenchyma segmentation model achieved a Dice coefficient of 87.17% on the internal test set and maintained consistent accuracy on the external cohort, with Dice coefficients ranging from 0.8509 to 0.9178. In the particularly challenging task of lymphocyte detection, the YOLOv7-based model attained an F1-score of 78.84% and mAP@0.5 of 81.16% on the test set, with performance sustained on external data. Critically, the automated TILs quantifications showed excellent agreement with independent pathologist assessments (ICC >0.96). The implementation of optimized lightweight architectures enables the pipeline to serve as an accessible solution for large-scale WSIs analysis in computational pathology.
    Conclusion: This study has successfully developed a fully automated annotation pipeline for lung adenocarcinoma WSIs. By generating high-quality annotations of stromal TILs, this pipeline establishes a reliable data foundation for subsequent computational pathology research and facilitates the advancement of artificial intelligence applications in pathology.
    Keywords:  automated annotation; deep learning; lung adenocarcinoma; pathology; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fbinf.2026.1764743
  5. F1000Res. 2025 ;14 814
    Prognostic Role of Absolute Monocyte Count, CD163⁺ Macrophages, and CD8⁺ Lymphocytes in Diffuse Large B-Cell Lymphoma Treated with R-CHOP.
    Faisal Syarifuddin, Anna Mira Lubis, Agnes Stephanie Harahap, Hamzah Shatri, Wulyo Rajabto, Imam Subekti, Rudy Hidayat, Sukamto Koesnoe.
       Background: Diffuse large B-cell lymphoma (DLBCL) exhibits heterogeneous clinical outcomes, including variations in event-free survival (EFS). Tumor microenvironment (TME) components, particularly absolute monocyte count (AMC), tumor-associated macrophages (TAMs), and tumor-infiltrating lymphocytes (TILs) have been implicated in prognosis, although findings remain inconsistent. This study evaluates the prognostic value of AMC, TAMs (CD163), and TILs (CD8) on two-year EFS in DLBCL patients treated with R-CHOP.
    Methods: A retrospective cohort study of 108 DLBCL patients treated from January 2014 to March 2021 was conducted. AMC was obtained from peripheral blood, while CD163 and CD8 expressions were analyzed via immunohistochemistry. Associations with two-year EFS were assessed using hazard ratios (HR), and correlations between AMC and tissue immune markers were evaluated.
    Results: High AMC and CD163 expression were significantly associated with poorer two-year EFS (HR = 9.82 and 8.57; both p < 0.001), whereas elevated CD8 expression predicted better outcomes (HR = 0.13; p < 0.001). AMC positively correlated with CD163 (r = 0.577; p < 0.001) and negatively with CD8 (r = -0.599; p < 0.001).
    Conclusion: AMC and CD163 are negative prognostic markers, while CD8 is protective. AMC may reflect the immune profile of the TME and serve as a practical prognostic biomarker in DLBCL.
    Keywords:  CD163; CD8; DLBCL; monocyte count; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.12688/f1000research.168760.2
  6. Gut Microbes. 2026 Dec 31. 18(1): 2652460
    Gut microbiota-associated nutritional-immune status predicts prognosis in postoperative NSCLC patients.
    Qian Yu, Anqi Chen, Junqi Yi, Majid Iqbal, Ziying Tang, Huabo Ge, Yan Hu, Wenliang Liu, Leliang Zheng, Jingqun Tang, Juanjuan Xiang.
       BACKGROUND: Surgical resection is the primary treatment for non-small cell lung cancer (NSCLC) patients with stages I and II; however, the postoperative prognosis varies among individuals. The prognostic nutritional index (PNI) reflects the nutritional-immune status of patients, but its microbial determinants remain unclear.
    METHODS: PNI was analyzed in a cohort of 372 retrospective and 139 prospective NSCLC patients. This analysis integrated gut microbiota signatures using 16S rRNA sequencing, fecal metabolomics, and murine fecal microbiota transplantation (FMT) models.
    RESULTS: A PNI value of ≥46.2 stratified postoperative NSCLC patients with improved 5-y survival (HR = 0.3889, 95% CI 0.2840-0.5356, p < 0.001). Patients with a high PNI showed enrichment of short-chain fatty acid (SCFA)-producing taxa, such as Akkermansia and Eubacterium hallii, and elevated butyrate/isovalerate levels, correlating with increased infiltration of CD8+ T cells (Pearson r = 0.51, p = 0.02). FMT from high-PNI patients reduced lung tumor growth in mice compared with FMT from low-PNI patients (7.2 vs 18 nodules, p = 0.01). Oral administration of A. muciniphila or/and E. hallii or butyrate suppressed tumor growth and enhanced CD8+ tumor-infiltrating lymphocytes (TILs) (p < 0.001).
    CONCLUSION: PNI and its linked gut microbiota‒SCFA axis are clinically prognostic biomarkers and potential immunomodulatory targets for early-stage NSCLC. Targeting this axis may serve as a promising coadjuvant strategy for NSCLC patients undergoing surgical resection.
    Keywords:  CD8+ T cells; NSCLC; SCFA; gut microbiota; prognostic nutritional index
    DOI:  https://doi.org/10.1080/19490976.2026.2652460
  7. Surg Oncol Clin N Am. 2026 04;pii: S1055-3207(25)00098-5. [Epub ahead of print]35(2): 191-205
    T-Cell Receptor Engineered T-Cell Therapy: A Rapidly Evolving Treatment Paradigm for Solid Tumors.
    Stav Leibou, Aaron J Dinerman, Nicholas D Klemen.
      Peripheral blood lymphocytes can be engineered to express T-cell receptors (TCRs) that recognize human leukocyte antigen (HLA)-restricted cancer antigens and subsequently administered systemically as TCR-T cell therapy. A growing repertoire of tumor-exclusive antigens including cancer germline antigens, viral oncoproteins, and neoantigens has led to a broadening potential applicability of this targeted approach in patients with solid tumors. While TCR-T cell therapy has already demonstrated clinical efficacy in trials of patients with metastatic melanoma and certain sarcomas, it is now emerging as a promising investigational therapy for mismatch repair proficient epithelial cancers.
    Keywords:  Adoptive cell transfer; Cancer immunotherapy; Immuno-oncology; TCR-T cells
    DOI:  https://doi.org/10.1016/j.soc.2025.12.001
  8. J Immunother Cancer. 2026 Apr 01. pii: e014601. [Epub ahead of print]14(4):
    Epigenetic remodeling in sarcoma promotes T-cell infiltration via modulation of the Hippo pathway.
    Mireia Cruz De Los Santos, Yi Chen, Amaia González De Zárate, Agnes Sorteberg, Honglei Zhao, Guillermo Vázquez-Cabrera, Neda Bigdeli, Solrun Kolbeinsdottir, Aarren Mannion, Lucas Baldran-Groves, Shi Yong Neo, Stina Linnea Wickström, Jeroen Melief, Lars Holmgren, Nikolas Herold, Felix Haglund de Flon, Andreas Lundqvist.
       BACKGROUND: Insufficient T-cell infiltration limits the effectiveness of immunotherapy in sarcoma, yet the tumor-intrinsic mechanisms that govern immune exclusion remain poorly defined.
    METHODS: By integrating patient-derived ex vivo sarcoma spheroids with autologous expanded tumor-infiltrating lymphocytes and an in vivo metastatic osteosarcoma model, antitumor immune regulation by histone modifications was examined.
    RESULTS: Histone H3 lysine 27 acetylation (H3K27ac) was identified as a key regulator of CD8+ T-cell infiltration in osteosarcoma and other bone and soft-tissue sarcomas. Pharmacological elevation of H3K27ac by the histone deacetylase 1/3 inhibitor entinostat promotes CD8+ T-cell activation, cytotoxicity, and the recruitment of CD8+CD103+ tissue-resident memory T cells. Mechanistically, these immune-boosting effects are triggered by a Hippo pathway switch, in which yes-associated protein 1 (YAP1) is suppressed, and vestigial-like family member 3 (VGLL3) is induced, thereby modulating transcription towards an immune-responsive state. Furthermore, we identified that VGLL3/CD103 signatures predict a response to anti-programmed cell death protein-1 (PD-1) treatment in patients with sarcoma, and that combining H3K27ac induction with anti-PD-1 further augments T cell-mediated killing in ex vivo autologous patient-derived spheroid models.
    CONCLUSIONS: Our findings reveal an epigenetic-Hippo-immunomodulatory axis in osteosarcoma that also extends to other sarcomas, providing a rationale for incorporating epigenetic preconditioning with immunotherapy to improve patient outcomes and pointing towards novel biomarkers for treatment guidance.
    Keywords:  Immunotherapy; Memory; Sarcoma; T cell; Tumor infiltrating lymphocyte - TIL
    DOI:  https://doi.org/10.1136/jitc-2025-014601
  9. Nat Commun. 2026 Mar 28.
    The CD4+ T cell population partners with Tpex CD8+ T cells to mediate antitumor immunity in the tumor microenvironment.
    Shota Takei, Satoshi Yamasaki, Ou Yamaguchi, Atsuto Mouri, Ayako Shiono, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Yoshinobu Ichiki, Hiroyuki Nitanda, Hirozo Sakaguchi, Tomoyuki Hishida, Katsuhisa Horimoto, Hiroshi Kagamu.
      CD4⁺ T cells support the priming, expansion, and function of CD8⁺ T cells through dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but the identity of their CD4⁺ T-cell partners remains unclear. Here, we perform scRNA-seq, scTCR-seq, and mass cytometry analysis on peripheral blood, tumor, and lymph nodes primarily from lung cancer patients and, in part, renal cell carcinoma. We identify an IL-7Rhigh CCR6⁺ Th1-like CD4⁺ T cell-population, named Th7R, that is numerically and spatially partnered with Tpex. Th7R cells express lymphotoxin-β and CXCL13, correlate with high endothelial venules, and co-localize with Tpex in tertiary lymphoid structures. Th7R cell abundance correlates with Tpex numbers in the TME and lymph nodes, and adoptive transfer of Th7R increases Tpex in a preclinical mouse model. Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.
    DOI:  https://doi.org/10.1038/s41467-026-71161-0
  10. Clin Exp Med. 2026 Mar 28. pii: 205. [Epub ahead of print]26(1):
    CXCL12-mediated T cell infiltration drives breast cancer metastasis.
    Xianfu Liu, Chunchun Chen, Lu Liu, Jingwei Tang, Hao Zhang, Gongsheng Jin, Yansong Chen.
      
    Keywords:  Breast cancer; CXCL10; CXCL12; T lymphocytes; TME
    DOI:  https://doi.org/10.1007/s10238-026-02126-2
  11. Stem Cell Res Ther. 2026 Mar 29.
    Preclinical efficacy of combination therapy with allogeneic induced pluripotent stem cell-derived invariant natural killer T and α-galactosylceramide-pulsed antigen-presenting cells.
    Takahiro Aoki, Midori Kobayashi, Momoko Okoshi, Munechika Yamaguchi, Hiroko Okura, Satoko Sasaki, Yoshie Sasako, Sachiko Kira, Yun-Hsuan Chang, Nayuta Yakushiji-Kaminatsui, Jafar Sharif, Masashi Matsuda, Masahiro Kiuchi, Kiyoshi Hirahara, Motoko Y Kimura, Shinichiro Motohashi, Haruhiko Koseki.
      Invariant natural killer T (iNKT) cells, upon activation, exhibit antitumor roles by bridging innate and acquired immunity. To overcome the challenges in producing iNKT cells from patients with cancer, we previously developed allogeneic human induced pluripotent stem cell-derived iNKT (iPSC-iNKT) cells. However, the activation of iPSC-iNKT cells by glycolipid ligands remains a critical step for iNKT cell-mediated cancer therapy. To show the effect of iPSC-iNKT cell-mediated antitumor immunity, in this preclinical study, by taking advantage of a human immune cell-transplanted patient-derived xenograft model using human IL-7/15 knock-in NSG mice, we demonstrate that a combination of iPSC-iNKT cells and α-galactosylceramide-pulsed antigen-presenting cells (αGalCer/APC) induces robust antitumor effects. Single-cell analysis of tumor-infiltrating lymphocytes revealed that this combination therapy uniquely expanded tumor-reactive memory-phenotype CD4 and CD8 T cells. Taken together, upon activation by αGalCer/APC, iPSC-iNKT cells are capable of effectively inducing antitumor T cell immunity, making them a promising tool for generating personalized antitumor T cell immunity.
    Keywords:  Acquired immunity; Invariant natural killer T cells; Patient-derived xenograft model; Preclinical study; Single-cell analysis; iPS cells; α-galactosylceramide
    DOI:  https://doi.org/10.1186/s13287-026-04994-7
  12. Cell Rep. 2026 Mar 27. pii: S2211-1247(26)00267-6. [Epub ahead of print]45(4): 117189
    Regulatory T cell-derived TGF-β signaling governs the differentiation and maintenance of tumor-infiltrating bystander CD8+ T cells.
    Yao Lin, Shuai Yue, Ding Qiu, Junjian He, Yang Yang, Shusen Ye, Wenwen Xi, Hairu Wang, Chunyang Xie, Texi Liang, Kaiyi Li, Xiaofan Yang, Yaxing Hao, Yuqing Li, Yi Yang, Teming Li, Song Wu, Lilin Ye, Xiangyu Chen.
      While indispensable for antitumor immunity, tumor-specific CD8+ T cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME). In contrast, bystander memory CD8+ T (TBYS) cells that recognize pathogen-derived antigens but not tumor antigens are abundant in tumors and maintain polyfunctional effector capacity, yet their differentiation and maintenance mechanisms remain unclear. Here, we demonstrate that CD8+ TBYS cells comprise a heterogeneous population of TCM, TEM, and TRM subsets defined by distinct chromatin accessibility and transcriptional programs. These subpopulations follow a progressive TCM→TEM→TRM differentiation trajectory during tumor progression, with TRM cells exhibiting superior tissue retention and ultimately dominating the TBYS pool. We further identify TGF-β-derived from regulatory CD4+ T cells as the central instructor of this hierarchical differentiation, which promotes TBYS cell accumulation through suppression of KLF2. Our study elucidates a key mechanism of TBYS cell differentiation and maintenance, providing a foundation for the improved immunotherapies targeting this population.
    Keywords:  CP: cancer; CP: immunology; KLF2; TGF-β; bystander T cell; regulatory T cell; tissue-resident memory T cell
    DOI:  https://doi.org/10.1016/j.celrep.2026.117189
  13. Nat Commun. 2026 Mar 31.
    Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models.
    Diego Figueroa, Juan Pablo Vega, Andrés Hernández-Oliveras, Felipe Ardiles, Sofía Hidalgo, Ximena López, Vicente Saavedra, Catalina Bustamante, Daniela Malavé, Felipe Flores, Felipe Gálvez-Cancino, Hugo Gonzalez, Manuel Varas-Godoy, Maria Rosa Bono, Fabiola Osorio, Vincenzo Borgna, Alvaro Lladser.
      Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8+ T cells that eradicate established murine tumors promote expansion of host CD8+ T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8+ T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8+ T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8+ T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.
    DOI:  https://doi.org/10.1038/s41467-026-71082-y
  14. Int Cancer Conf J. 2026 Apr;15(2): 284-294
    Unique pattern of endometrial invasion in gastric-type adenocarcinoma of the uterine cervix: a report of two cases.
    Kyosuke Kamijo, Tsutomu Miyamoto, Hirofumi Ando, Hisanori Kobara, Yayoi Satoh, Yaeko Kobayashi, Tanri Shiozawa.
      Gastric-type cervical adenocarcinoma (GAS), the most prevalent subtype of human papillomavirus (HPV)-independent cervical adenocarcinoma, is an aggressive malignancy with a poor prognosis. We herein present two cases of GAS with a unique endometrial infiltration pattern. Both cases were 37-year-old nulligravid women presenting with advanced GAS. A pathological examination revealed HPV-independent GAS that was positive for claudin 18 and negative for p16, with extensive invasion, including the myometrium and endometrium. Endometrial infiltration was characterized by a distinctive "symbiotic" pattern of invasion. In these areas, GAS glands intermingled with normal endometrial glands without disrupting the native architecture, and there was no distinct tumor border or stromal reaction. An immunohistochemical analysis revealed fewer CD8-positive tumor-infiltrating lymphocytes (TILs) around invasive GAS glands in the endometrium than in the normal endometrium and both the tumor center and invasive margin of the primary cervical lesion. These results are consistent with relative T-cell exclusion at the tumor-endometrium interface. This "symbiotic" invasion pattern differs from typical cervical adenocarcinoma, which forms distinct boundaries with desmoplastic stromal reactions. The observed pattern may contribute to the unexpectedly extensive spread of GAS frequently discovered only after surgical resection. The reduction in CD8-positive TILs density around invasive GAS glands indicates an immunologically "cold" tumor microenvironment that may contribute to treatment resistance. The present results provide novel insights into the pathology of GAS that may inform more effective diagnostic approaches and therapeutic strategies for this aggressive malignancy.
    Keywords:  Cervical cancer; Endometrial invasion pattern; Gastric-type adenocarcinoma; Human papillomavirus-independent; Radical hysterectomy
    DOI:  https://doi.org/10.1007/s13691-026-00858-2
  15. Cancer Immunol Immunother. 2026 Apr 02. pii: 134. [Epub ahead of print]75(4):
    Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling.
    Zhengchun Kang, Xu Li, Xiuzhu Ma, Feihu Yan, Zhen Wang.
      Activation of the T cell receptor (TCR) complex is fundamental to initiating adaptive immune responses, particularly in CD8⁺ cytotoxic T lymphocytes that mediate anti-tumor immunity. However, the immunosuppressive tumor microenvironment often impairs TCR signaling, limiting the efficacy of T cell-based cancer immunotherapies. Here, we report the identification of rosmarinic acid (RA), a naturally occurring polyphenolic compound, as a potent small molecule enhancer of TCR signaling. RA significantly augments IL-2 and IFN-γ production, promotes T cell proliferation, and enhances cytotoxicity of CD8⁺ T cells in vitro. Mechanistically, RA directly binds to MEK1, a key kinase in the MAPK/ERK pathway, with high affinity, leading to reduced MEK1 phosphorylation and downstream signaling activation. Transcriptomic and metabolic profiling of RA-treated CD8⁺ T cells revealed upregulation of genes associated with TCR signaling, calcium flux, PPAR signaling, and oxidative phosphorylation, indicating a broad remodeling of T cell effector function and metabolism. In vivo, RA treatment significantly suppressed tumor growth, increased tumor-infiltrating lymphocyte (TIL) frequency, and improved survival in MC38 tumor-bearing mice. These effects were abrogated upon CD8⁺ T cell depletion, confirming their central role. Furthermore, RA synergized with anti-PD-1 therapy and enhanced the efficacy of adoptively transferred OT-I T cells in colorectal tumor-bearing hosts. Collectively, our findings reveal RA as a novel immunomodulatory agent that boosts CD8⁺ T cell responses via MEK1-mediated TCR signaling enhancement, providing a promising strategy for drug repurposing in cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Drug repurposing; MEK1; Rosmarinic acid; T cell receptor
    DOI:  https://doi.org/10.1007/s00262-026-04366-3
  16. bioRxiv. 2026 Mar 23. pii: 2026.03.19.712729. [Epub ahead of print]
    Safety and Feasibility of Infusing Ex Vivo Expanded Allogeneic Canine Natural Killer Cells for the Treatment of Metastatic Solid Tumors.
    Allison M Weisnicht, Fernanda Szewc, Monica Moonkyung Cho, Han-Yun Hannah Cheng, Swetha Ganesh, Lauren Mahoney, Kathryn Fox, Portia R Smith, Mallery Olsen, Rebecca M Richards, David M Vail, Christian M Capitini.
       Background: Companion canines need advances in therapeutic options for solid tumor malignancies. Prior studies established feasibility of autologous natural killer (NK) cell infusions in canines with solid tumors; however, autologous products are limited by dysfunctional immunity and a manufacturing process that delays care. Allogeneic NK cells offer the possibility of "off-the-shelf" therapy to be administered from healthy donors.
    Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy canine donors via density gradient separation. NK cells were expanded with recombinant human IL-2 and canine IL-21 with the addition of K562 feeder cells transfected with CD137 ligand and membrane bound human IL-15. Additional experiments included IL-12 in the expansions. In vitro potency was assessed via co-culture with the D17-mKate2 canine osteosarcoma cell line. Three canines were enrolled in a phase 1 trial infusing ex vivo expanded allogeneic NK cells after lymphodepletion.
    Results: Flow cytometric analysis confirmed successful expansion of canine NK cells with up to 50% of cells demonstrating NKp46+ after 14 days of expansion. Residual T cell numbers varied based on donor. The addition of IL-12 led to increased NK cell expansion. Incucyte demonstrated potency with increasing osteosarcoma cell death at higher effector to target ratios. Three canines with metastatic/refractory solid tumors were successfully lymphodepleted and infused with allogeneic NK cell products. The canines tolerated the infusions well.
    Conclusions: Canine allogeneic NK cells were successfully expanded and activated ex vivo, demonstrated potency in vitro, and safety in vivo. Further studies will optimize the NK cell product and escalate dosing to reach the maximal tolerable dose.
    DOI:  https://doi.org/10.64898/2026.03.19.712729
  17. Cell Rep. 2026 Apr 01. pii: S2211-1247(26)00243-3. [Epub ahead of print]45(4): 117165
    Unveiling the molecular architecture of T cells and immune synapses with cryo-expansion microscopy.
    Florent Lemaître, Olivier Mercey, Isabelle Mean, Elise Paulin, Valérie Dutoit, Jan A Rath, Christine von Gunten, Denis Migliorini, Caroline Arber, Paul Guichard, Virginie Hamel, Benita Wolf.
      Cytotoxic T cell killing is executed at the immunological synapse, whose nanoscale organization underlies function but remains difficult to resolve in native states. Here, we apply cryo-expansion microscopy (cryo-ExM) to visualize the near-native three-dimensional architecture of human T cell synapses and cytotoxic organelles. Cryo-ExM preserves actin, microtubules, membranes, and fine membrane protrusions with high fidelity, enabling volumetric quantification of synapse morphogenesis. We identify an adhesion-dependent, dome-like membrane architecture beneath activated T cells that collapses upon ICAM-1 engagement, linking synapse topology to adhesive cues. Cryo-ExM further resolves intact lytic granules in primary human CD4 and CD8 T cells, revealing single-core and multi-core ultrastructures, spatial organization, and perforin and granzyme loading. Using tissue-adapted expansion microscopy, we map cytotoxic granule content in tumor-infiltrating T cells in FFPE human brain tumors. Together, these data establish a near-native structural framework for human T cell cytotoxicity and an imaging workflow bridging cell models and clinical tissues.
    Keywords:  3D ultrastructure; CP: immunology; T cell cytotoxicity; cryo-expansion microscopy; cytotoxic granule deployment; immune synapse; lytic granules; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.celrep.2026.117165
  18. J Thorac Oncol. 2026 Mar 26. pii: S1556-0864(26)00146-2. [Epub ahead of print] 103693
    Brief Report: Low Delta-like Ligand 3 expression and T Cell Exhaustion Drive Resistance to Tarlatamab combined with anti-PD-1 in Small-Cell Lung Cancer.
    Akito Fukuda, Tomoyo Fukami, Kotaro Nomura, Jumpei Kashima, Shogo Kumagai, Yasushi Goto, Yasushi Yatabe, Tatsuya Yoshida.
       INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis. Tarlatamab, a bispecific T cell engager that targets CD3 and delta-like ligand 3 (DLL3), is the standard of care for patients with previously treated SCLC. However, the mechanisms underlying acquired tarlatamab resistance remain unclear.
    METHODS: We assessed two patients with extensive-stage SCLC treated with tarlatamab and an anti-programmed cell death protein 1 (PD-1) antibody in a phase 1b clinical trial (jRCT: 2051240045). We analyzed tumor biopsy samples obtained at baseline and at time of progressive disease using multiplexed immunohistochemistry (mIHC).
    RESULTS: Pathological analysis of post-resistance specimens revealed a phenotypic shift in both cases, characterized by tumor cells with abundant cytoplasm and reduced synaptophysin expression levels. mIHC revealed low DLL3 expression on tumor cells at time of progression. Additionally, exhausted CD8+ T cells expressing PD-1+, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and/or lymphocyte-activation gene 3 (LAG3), and immunosuppressive cells, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) regulatory T cells and CD206+ M2 tumor-associated macrophages, were significantly more abundant in the tumor microenvironment (TME) than that in samples obtained before tarlatamab plus anti- PD1combination therapy.
    CONCLUSIONS: Acquired resistance to tarlatamab plus anti-PD-1 in SCLC was associated with low DLL3 antigen expression particularly in the setting of phenotypic switch to a non-small cell lung cancer morphology and an increasingly immunosuppressive TME. Therefore, combination strategies that incorporate immune checkpoint blockade or myeloid-targeted therapies may be warranted to enhance treatment outcomes.
    Keywords:  acquired resistance; immunotherapy; small cell lung cancer; tarlatamab
    DOI:  https://doi.org/10.1016/j.jtho.2026.103693
  19. J Nat Prod. 2026 Mar 30.
    Activity of Didesmethylrocaglamide in High Grade Serous Ovarian Cancer Using Preclinical In Vitro and In Vivo Models.
    Elizabeth N Kaweesa, Nicole Benson, Tyler A Wilson, Ermias Mekuria Addo, Jane Miglo, Jaqueline M Bazioli, Daniel D Lantvit, Garima Agarwal, A Douglas Kinghorn, James R Fuchs, Joanna E Burdette.
      High grade serous ovarian cancer (HGSOC) is the most lethal gynecological cause of death in women and requires new treatments to help tackle chemoresistance. Rocaglamides, a promising class of anticancer natural products, function as protein translation inhibitors and trigger apoptosis in other types of solid tumors. Didesmethylrocaglamide ((±)-DDR), a derivative of rocaglamide with potent antitumor activity, was synthesized, including three additional rocaglamide derivatives, (±)-DDR01, (±)-DDR03, and (±)-DDR04, to evaluate their cytotoxicity in HGSOC. Using in vitro models, it was determined that (±)-DDR induced cytotoxicity in ovarian cancer cell lines as early as 24 h after application and activated caspase-3, indicating pro-apoptotic activity. In addition, (±)-DDR was cytotoxic in the PE04 and MCF7-ADR (OVCAR8-RES) cell lines that are resistant to cisplatin and paclitaxel, respectively. Evaluation of each enantiomer revealed the minus enantiomer to be ∼18-fold more potent compared to the plus enantiomer in the OVCAR8 cell line. (-)-DDR was further evaluated using an OVCAR8 xenograft model in mice, and a reduction in tumor burden was observed. Its effective cytotoxicity in drug-sensitive and -resistant cell models suggests that (±)-DDR and its corresponding minus enantiomer may have potential as a new therapeutic strategy against HGSOC.
    DOI:  https://doi.org/10.1021/acs.jnatprod.5c01544
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