bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–05–25
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Prognostic Significance of Regulatory CD25+ T Cells in Bladder Cancer: An Immunohistochemical Analysis.
  2. Advances in TIL therapy: Expanding the horizons beyond melanoma.
  3. Correlation study of tumor-infiltrating lymphocytes (TILs) and subtypes analysis before and after neoadjuvant chemotherapy in triple-negative breast cancer.
  4. Clinicopathological Characterization of Squamous Cell Lung Carcinoma Adjacent to Emphysema.
  5. Assessment of inflammatory infiltrate in colorectal carcinoma with a critical evaluation of the different scoring systems and correlation with prognostic parameters.
  6. High-Sensitivity PD-L1 Staining Using Clone 73-10 Antibody and Spatial Transcriptomics for Precise Expression Analysis in Non-Tumorous, Intraepithelial Neoplasia, and Squamous Cell Carcinoma of Head and Neck.
  7. Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer.
  8. Unraveling SET: Exploring ovarian high-grade serous carcinoma and its BRCA1/2 immunoexpression.
  9. Benefit from huCAR19-IL18 cells in patients with CD19+ lymphomas after CAR T cells.
  10. Resistance to TIL therapy in lung cancer mediated by clonal T cell loss and neoantigen escape.
  11. Spatio-temporal T cell tracking for personalized TCR-T designs in childhood cancer.
  12. Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery.
  13. Adaptive Immune Response and PD-1/ PD-L1 Status in Chemotherapy Treated High Grade Serous Carcinoma is Dependent on Chemotherapy Response Score.
  14. Reimagining the Therapeutic Approach for Anaplastic Thyroid Cancer: The Roadmap to a Cure.
  15. S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.
  16. Standardized Flow Cytometry Method for Absolute Counting of Intraepithelial Lymphocytes in the Intestinal Mucosa Using TruCountTM Beads.
  17. TCR-based therapy directed against kallikrein-related peptidase 4 is safe and effective against prostate cancer.
  18. Beyond Canonical Immune Checkpoints: Overexpression of TNFRSF Members 4-1BB and OX-40 Marks T Cells Exhibiting Phenotypic Features of Exhaustion in Cervical Carcinoma.
  19. Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.
  20. Editorial: Enhancing T cell function: innovations in cancer immunotherapy.
  1. Turk Patoloji Derg. 2025 ;1(1):
    Prognostic Significance of Regulatory CD25+ T Cells in Bladder Cancer: An Immunohistochemical Analysis.
    Sarra Ben Rejeb, Nadia Kouki, Hassen Khouni, Rami Boulma, Khadija Bellil.
       OBJECTIVE: Tumor-infiltrating lymphocytes (TILs) have been shown to predict outcomes in several cancers. This study aimed to evaluate the density and location of regulatory T cells (Tregs) using immunohistochemistry (IHC) in urothelial carcinomas (UC) of the bladder and to assess their prognostic value.
    MATERIAL AND METHODS: We have retrospectively collected all cases of UC of the bladder infiltrating at least the lamina propria, diagnosed in our pathology department between 2011-2021. Specimens were stained for CD3 and CD25. TILs were assessed separately in the tumor core and the stroma. The median TIL count was used as a cut-off to classify cases into low- or high-density groups.
    RESULTS: A total of 30 cases were included in the study. The median age of the patients was 65 years, with a male-to-female ratio of 9:1. The distribution of TILs was heterogeneous across locations among patients. CD3+ (p=0.035) and CD25+ (p=0.051) TILs were predominantly observed in the stroma. The density of CD25+ and CD3+ TILs were not associated with clinicopathological features. Multivariate analysis revealed that advanced histological stage and a high density of regulatory CD25+ T lymphocytes were predictive factors of poorer event-free survival (respectively p=0.041 and p=0.052).
    CONCLUSION: Regulatory T cells appear to predict worse survival outcomes. Further studies are needed to confirm their prognostic value.
    DOI:  https://doi.org/10.5146/tjpath.2025.13848
  2. Med. 2025 May 10. pii: S2666-6340(25)00129-1. [Epub ahead of print] 100702
    Advances in TIL therapy: Expanding the horizons beyond melanoma.
    Pauline Wiertsema, Ya Hwee Tan, John B A G Haanen, Tom T P Seijkens, Inge Jedema.
      Tumor-infiltrating lymphocyte (TIL) therapy represents a breakthrough in solid tumor treatment, addressing unmet needs for patients with limited options. While its efficacy is established in advanced melanoma, TIL therapy shows early promise in non-small cell lung cancer, breast cancer, gynecological cancers, and head and neck cancers. However, challenges such as reduced T cell infiltration, lower tumor mutational burden (TMB), immunosuppressive tumor microenvironments (TME), and toxicity associated with the TIL therapy regimen hinder its broader application in these patient groups, compared with melanoma. To address these challenges, new approaches focus on the selection of tumor-reactive TIL, optimization of TIL expansion, combination of immune checkpoint inhibitors with TIL therapy to counteract immunosuppressive microenvironments, and genetic modification of TIL to enhance persistence and functionality. Larger clinical trials are essential to validate these innovations and standardize protocols. With continued advancements, TIL therapy has the potential to redefine the treatment landscape for advanced solid cancers.
    DOI:  https://doi.org/10.1016/j.medj.2025.100702
  3. Gland Surg. 2025 Apr 30. 14(4): 628-645
    Correlation study of tumor-infiltrating lymphocytes (TILs) and subtypes analysis before and after neoadjuvant chemotherapy in triple-negative breast cancer.
    Yan Zhao, Si-Juan Jiang, Jin-Lu Wang, Zong-Yu Xie, Xin Jin.
       Background: In recent years, neoadjuvant chemotherapy (NACT) has become an increasingly important treatment for triple-negative breast cancer (TNBC). As the most immunogenic subtype of breast cancer, it is imperative to comprehensively study the immune microenvironment of TNBC and the effects of NACT on it. Our study aims to address this need and provide valuable insights for the development of effective postoperative adjuvant treatment strategies.
    Methods: Samples were taken prior to and following NACT with docetaxel, epirubicin, and cyclophosphamide (TEC) from 71 TNBC patients who were included in this trial. We examined the clinicopathological alterations in patients before and after NACT treatment, assessed the impact of stromal tumor-infiltrating lymphocytes (sTILs) and immune biomarkers [CD8, CD4, CD3, FOXP3, CD20, CD163, programmed cell death ligand 1 (PD-L1)] on the efficacy of neoadjuvant therapy, and identified changes in NACT-induced immune subsets and specific immune biomarkers.
    Results: Our study revealed that tumor size, histological grade, Ki-67 status, and sTILs content in baseline clinical features, as well as CD3, CD4, and CD8 content before NACT, showed significant differences between pathological complete response (pCR) and non-pCR patients (P<0.05). The expression of sTILs and PD-L1 in residual lesions after NACT was found to be higher than before NACT. Univariate analysis indicated that the levels of sTILs, CD3, CD4, and CD8 immune subsets before NACT were correlated with pCR. Importantly, multivariate regression analysis demonstrated that sTILs and CD8 immune subsets before NACT served as independent predictors of TNBC neoadjuvant therapy (P<0.05), providing crucial insights into the individualized management of TNBC.
    Conclusions: The findings of this study suggest that increasing sTILs and CD8 can significantly enhance the neoadjuvant efficacy of TNBC. Furthermore, the addition of CD3 and CD8 immune subsets can substantially improve the efficacy of TNBC neoadjuvant prediction. The detection of relevant immune markers after neoadjuvant therapy holds great promise in providing more comprehensive and accurate prognostic and therapeutic information for TNBC patients.
    Keywords:  Triple-negative breast cancer (TNBC); immune cell subset; neoadjuvant chemotherapy (NACT); programmed cell death ligand 1 (PD-L1); tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.21037/gs-2024-537
  4. Pathol Int. 2025 May 21.
    Clinicopathological Characterization of Squamous Cell Lung Carcinoma Adjacent to Emphysema.
    Tetsuya Sakai, Hibiki Udagawa, Hiroki Izumi, Shigeki Umemura, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Naito Tomoyuki, Nakai Tokiko, Tetsuro Taki, Naoya Sakamoto, Shingo Sakashita, Motohiro Kojima, Masahiro Tsuboi, Koichi Goto, Genichiro Ishii.
      The study investigated the clinicopathological features and characteristic immune tumor microenvironment (TME) of lung squamous cell carcinoma (SqCC) adjacent to emphysematous lesions. 184 consecutive patients with peripheral-type SqCC who had undergone complete surgical resection were enrolled. The clinicopathological differences between emphysema-adjacent SqCC (EA-SqCC) and non-emphysema-adjacent SqCC (non-EA-SqCC) were examined. The immune TME, including tumor-infiltrating lymphocytes (TILs) and PD-L1 expression, was also analyzed. EA-SqCC was detected in 132 (71.7%) of the 184 patients. Patients with EA-SqCC had shorter recurrence-free survival (RFS) [median 58.2 months vs. not Reached (NR); hazard ratio (HR) 0.47; 95% CI 0.25-0.81, p < 0.01] and tended to have shorter overall survival (NR vs. NR; HR 0.47; 95% CI 0.27-1.03, p = 0.07) compared to patients with non-EA-SqCC. Evaluation of TILs in the cancer stroma showed the number of Foxp3+ TILs in the EA-SqCC group was significantly higher than that in the non-EA-SqCC group (median number 58 vs. 43, p < 0.01). However, there were no significant differences in the number of CD8 + T cells and the PD-L1 expression between the two groups. Immunosuppressive microenvironment is a characteristic feature of EA-SqCC, which may contribute to the poor prognosis of this disease.
    Keywords:  emphysema; lung cancer; programmed cell death ligand‐1; squamous cell carcinoma; tumor microenvironment; tumor‐infiltrating lymphocytes
    DOI:  https://doi.org/10.1111/pin.70023
  5. Indian J Pathol Microbiol. 2025 May 22.
    Assessment of inflammatory infiltrate in colorectal carcinoma with a critical evaluation of the different scoring systems and correlation with prognostic parameters.
    Swagata Dowerah, Pranita Medhi, Dhrubajyoti Borgohain, Gobil Thapa, Anjali Daimary.
       INTRODUCTION: The prognostic significance of tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) has been recognized for a long time; yet, there is lack of a standardized scoring system to assess the inflammatory infiltrate which is universally acceptable. We therefore undertook a 1-year retrospective study on CRC to study type of inflammatory reaction in colorectal carcinoma, compare the different scoring systems for tumor immune response, and correlate the local inflammatory response to prognostic parameters.
    MATERIALS AND METHODS: A 1-year retrospective study was conducted on archival slides of cases diagnosed with colorectal carcinoma. he inflammatory response was assessed at the invasive margin (IM) as well as within tumor tissue, including stromal inflammatory infiltrate, and quantified using Klintrup-Makinen (K-M) score, Jass score, Crohn's-like reaction, and the International TILs Working Group (ITWG) scoring. The intensity of the inflammatory reaction was correlated with the grade of the tumor, the pT stage, lymph node metastasis, tumor location, and tumor size.
    RESULTS: We studied 49 cases of colorectal carcinoma over a period of 1 year with a male-to-female (M:F) ratio of 1.45:1. Proximal colon was the most common site followed by distal colon and rectum. About 77.6% of cases were of low histologic grade, while 22.4% were high-grade tumors. About 18.4% were T1 tumors, 44.9% were T2, 28.6% were T3 tumors, and the remaining 8.2% were T4. In the ITWG system, the TIL response was statistically significant for T stage of the tumor. In the Klintrup-Makinen system, a higher score corresponded with a lower histological grade and this difference was found to be statistically significant. Both the Jass score and Crohn's-like reaction did not show any correlation with the prognostic parameters evaluated in the study. The neutrophil score did not show any significant difference among the prognostic categories. Eosinophils were seen in 43% of cases of CRC, while macrophages were seen in only 2% of cases. Necrosis was absent in 67.3% of cases, focal in 18.4% of cases, moderate in 6.1% of cases, and extensive in 8.2% of cases.
    CONCLUSION: A higher intensity of the inflammatory response correlates with a lower grade/T stage of the tumor. As such, the adoption of a uniform system of reporting the inflammatory response could be of immense benefit in prognostication and treatment of the cases of colorectal carcinoma.
    Keywords:  Colorectal cancer; inflammatory reaction; scoring
    DOI:  https://doi.org/10.4103/ijpm.ijpm_307_24
  6. Head Neck Pathol. 2025 May 20. 19(1): 65
    High-Sensitivity PD-L1 Staining Using Clone 73-10 Antibody and Spatial Transcriptomics for Precise Expression Analysis in Non-Tumorous, Intraepithelial Neoplasia, and Squamous Cell Carcinoma of Head and Neck.
    Yuri Noda, Naho Atsumi, Takeo Nakaya, Hiroshi Iwai, Koji Tsuta.
       PURPOSE: While immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have improved outcomes in head and neck squamous cell carcinoma (HNSCC), eligibility criteria based on immunohistochemistry (IHC) target PD-1 solely. We aimed to evaluate the PD-L1 (CD274) expression using highly sensitive clone 73 - 10 and spatial transcriptomics (ST) analysis to elucidate the role of PD-L1 in HNSCC and thus potentially expand the pool of eligible patients.
    METHODS: Immunohistochemical staining of 73 - 10, CD3, CD4, and CD8 were performed in 94 HNSCC clinical samples along with paired adjacent squamous intraepithelial neoplasm (SIN) and normal oral mucosa (NOM) samples. The 73 - 10 positivity was evaluated using a tumor cell score ≥ 1%, and the results were analyzed against clinicopathological features including CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs), and clinical outcomes. Furthermore, ST and PD-L1 related pathway analysis was performed in 6 paired HNSCC, SIN and NOM samples.
    RESULTS: The 73 - 10 detected-PD-L1 positivity was high in HNSCC (79%) compared to SIN (10%) and NOM (3%). 73 - 10+ correlated with high CD4+ TILs, as well as the independent prognostic factor of OS, DSS, and PFS of HNSCC (all p < 0.05). ST analysis revealed that the upregulated distribution of CD274 correlated with 73 - 10 positivity. Pathway analysis revealed a significant upregulation of CD274 and CD4 in HNSCC compared to SIN and NOM, and HIF-1α and IFN-γ as key regulators of PD-L1 expression in HNSCC.
    CONCLUSION: Clone 73 - 10 is a relatively suitable candidate for identifying patients with PD-L1 expression eligible for ICI therapy. It demonstrates high sensitivity in detecting PD-L1 (CD274) in HNSCC, offering immunological and prognostic insights.
    Keywords:  73 − 10; Head and Neck squamous cell carcinoma; Immune checkpoint inhibitor; Oral; PD-L1
    DOI:  https://doi.org/10.1007/s12105-025-01798-8
  7. Front Immunol. 2025 ;16 1554871
    Recent advances in biomarkers for predicting the efficacy of immunotherapy in non-small cell lung cancer.
    Jiacheng Zhang, Zehao Song, Yuanjie Zhang, Chentong Zhang, Qi Xue, Guochao Zhang, Fengwei Tan.
      Lung cancer continues to be the primary cause of cancer-related deaths globally, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all instances. Recently, immune checkpoint inhibitors (ICIs) have transformed the treatment approach for NSCLC, however, only a subset of patients experiences significant benefits. Therefore, identifying reliable biomarkers to forecast the efficacy of ICIs is crucial for ensuring the safety and effectiveness of treatments, becoming a major focus of current research efforts. This review highlights the recent advances in predictive biomarkers for the efficacy of ICIs in the treatment of NSCLC, including PD-L1 expression, tertiary lymphoid structures (TLS), tumor-infiltrating lymphocytes (TILs), tumor genomic alterations, transcriptional signatures, circulating biomarkers, and the microbiome. Furthermore, it underscores the pivotal roles of liquid biopsy, sequencing technologies, and digital pathology in biomarker discovery. Special attention is given to the predictive value of TLS, circulating biomarkers, and transcriptional signatures. The review concludes that the integration of multiple biomarkers holds promise for achieving more accurate efficacy predictions and optimizing personalized immunotherapy strategies. By providing a comprehensive overview of the current progress, this review offers valuable insights into biomarker-based precision medicine for NSCLC and outlines future research directions.
    Keywords:  NSCLC; biomarker; circulating biomarkers; immune checkpoint inhibitors; tertiary lymphoid structures
    DOI:  https://doi.org/10.3389/fimmu.2025.1554871
  8. Indian J Pathol Microbiol. 2025 May 22.
    Unraveling SET: Exploring ovarian high-grade serous carcinoma and its BRCA1/2 immunoexpression.
    Anubhuti Chaturvedi, Varuna Mallya, Shramana Mandal, Y M Mala.
       INTRODUCTION: BRCA1 and BRCA2 (breast cancer type 1 and 2 susceptibility protein antibody) dysfunction, frequently seen in ovarian high-grade serous carcinomas (HGSC), often results from germline mutations, somatic mutations, and promoter methylation. Identification of tumors with BRCA defects has therapeutic and prognostic implications.
    MATERIALS AND METHODS: Our goal was to assess the clinicopathological characteristics and significance of solid, pseudoendometrioid, and transitional (SET) ovarian HGSC and to correlate these with BRCA1 and 2 immunoexpression.
    RESULT: Of the total 45 HGSC cases assessed, SET growth pattern was seen in 64.4% (29/45) cases. Furthermore, 35.5% (16/45) of the total cases showed BRCA1 loss, and 17.7% (8/45) cases showed BRCA2 loss. Tumor-infiltrating lymphocytes (TILs), necrosis, lymphovascular invasion, and BRCA1 loss positively correlated with SET pattern morphology.
    CONCLUSION: Immunohistochemical analysis for BRCA1 is an effective and alternative method for the detection of BRCA1 dysfunction and can be correlated with the histomorphological pattern of HGSC.
    Keywords:  ; SET pattern; ovarian carcinoma
    DOI:  https://doi.org/10.4103/ijpm.ijpm_575_24
  9. Nat Rev Clin Oncol. 2025 May 23.
    Benefit from huCAR19-IL18 cells in patients with CD19+ lymphomas after CAR T cells.
    Diana Romero.
      
    DOI:  https://doi.org/10.1038/s41571-025-01036-8
  10. Nat Cancer. 2025 May 21.
    Resistance to TIL therapy in lung cancer mediated by clonal T cell loss and neoantigen escape.
      
    DOI:  https://doi.org/10.1038/s43018-025-00947-w
  11. Ann Oncol. 2025 May 20. pii: S0923-7534(25)00733-1. [Epub ahead of print]
    Spatio-temporal T cell tracking for personalized TCR-T designs in childhood cancer.
    I Sentís, J L Melero, A Cebria-Xart, M Grzelak, M Soto, A Michel, Q Rovira, C J Rodriguez-Hernandez, G Caratù, A Urpi, C Sauvage, A Mendizabal-Sasieta, D Maspero, C E Lavarino, A Pascual-Reguant, A Castañeda Heredia, J P Muñoz Perez, J Mora, A Harari, J C Nieto, A Avgustinova, H Heyn.
       BACKGROUND: Immune checkpoint inhibition (ICI) has revolutionized oncology, offering extended survival and long-term remission in previously incurable cancers. While highly effective in tumors with high mutational burden, lowly mutated cancers, including pediatric malignancies, present low response rate and limited predictive biomarkers.
    PATIENTS AND METHODS: We present a framework for the identification and validation of tumor-reactive T cells as a biomarker to quantify ICI efficacy and as candidates for a personalized TCR-T cell therapy. Therefore, we profiled a pediatric malignant rhabdoid tumor patient with complete remission after ICI therapy using deep single-cell T cell receptor (TCR) repertoire sequencing of the tumor microenvironment (TME) and the peripheral blood.
    RESULTS: Tracking T cell dynamics longitudinally from the tumor to cells in circulation over a time course of 12 months revealed a systemic response and durable clonal expansion of tumor-resident and ICI-induced TCR clonotypes. We functionally validated tumor reactivity of TCRs identified from the TME and the blood by co-culturing patient-derived tumor cells with TCR-engineered autologous T cells. Here, we observed unexpectedly high frequencies of tumor-reactive TCR clonotypes in the TME and confirmed T cell dynamics in the blood post-ICI to predict tumor-reactivity.
    CONCLUSION: These findings strongly support spatio-temporal tracking of T cell activity in response to ICI to inform therapy efficacy and to serve as a source of tumor-reactive TCRs for personalized TCR-T designs.
    Keywords:  Clonotype tracking; Immune checkpoint inhibition; Malignant rhabdoid tumor; Single cell sequencing; T cell receptor sequencing; T cell therapy
    DOI:  https://doi.org/10.1016/j.annonc.2025.05.530
  12. bioRxiv. 2025 May 19. pii: 2025.04.04.647304. [Epub ahead of print]
    Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery.
    John P Murad, Lea Christian, Reginaldo Rosa, Yuwei Ren, Eric Hee Jun Lee, Lupita S Lopez, Anthony K Park, Jason Yang, Candi Trac, Lauren N Adkins, Wen-Chung Chang, Catalina Martinez, Carl H June, Stephen J Forman, Jun Ishihara, John K Lee, Lawrence A Stern, Saul J Priceman.
      CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGFβtrap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., αPDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGFβtrap, IL15, or IL12 molecules fused to αPDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with αPDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with αPDL1 fused with TGFβtrap or IL15. Further, αPDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFNγ production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our αPDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.
    DOI:  https://doi.org/10.1101/2025.04.04.647304
  13. Hum Pathol. 2025 May 17. pii: S0046-8177(25)00087-5. [Epub ahead of print] 105800
    Adaptive Immune Response and PD-1/ PD-L1 Status in Chemotherapy Treated High Grade Serous Carcinoma is Dependent on Chemotherapy Response Score.
    Christine H Miller, Anusha Vemuri, Ernst Lengyel, Ricardo R Lastra.
       BACKGROUND: Platinum-based chemotherapy and debulking surgery is the standard of care for patients with advanced tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response scoring (CRS) system is a histopathologic scoring system developed to measure response to neoadjuvant chemotherapy with prognostic implications. Omental samples with high CRS have greater inflammatory cell infiltrates, but the immunophenotype of infiltrating immune cells and PD-L1 expression of the residual tumor has not been well-defined.
    DESIGN: Twenty cases of patients with FIGO stage IIIA to IIIC HGSC undergoing interval debulking after receiving 3-4 rounds of chemotherapy were selected. 6/20 cases of omental samples were graded as CRS 1, 7/20 were graded CRS 2, and 7/20 were graded CRS 3. The following immunohistochemical stains were performed: CD8, CD4, Foxp3, PD1, and PD-L1. The total number of tumor-infiltrating lymphocytes was recorded, and each case was given a PD-L1 combined positive score (CPS) and tumor proportion score (TPS).
    RESULTS: There was a significantly greater number of CD8+ T cells, PD-1+ T cells, CD4+ T cells, and Foxp3+ T cells in CRS 3-scored cases compared to CRS 1 scored cases (p-values 0.0018, 0.0224, 0.0071, and 0.0136, respectively). CRS 3-scored cases had a greater PD-L1 CPS (CRS 3 CPS 13 +/- 8.2 versus CRS 1 CPS 0 +/- 0; p-value 0.0485).
    CONCLUSIONS: Tubo-ovarian high-grade serous carcinoma with greater response to neoadjuvant treatment have significantly greater T cell infiltrate and greater PD-L1 combined positive score, highlighting a potential role of the CRS as a predictive biomarker for immune checkpoint blockade therapy.
    DOI:  https://doi.org/10.1016/j.humpath.2025.105800
  14. Thyroid. 2025 May;35(5): 462-470
    Reimagining the Therapeutic Approach for Anaplastic Thyroid Cancer: The Roadmap to a Cure.
    Maria E Cabanillas, Neal Akhave, Victoria Banuchi, Naifa Busaidy, Ramona Dadu, Renata Ferrarotto, Gary B Gunn, Sarah Hamidi, Marie-Claude Hofmann, S Mohsen Hosseini, Priyanka C Iyer, Stephen Y Lai, Anna Lee, Anastasios Maniakas, Matthew S Ning, Michael Spiotto, Jennifer R Wang, Michelle D Williams, Mark Zafereo.
      Background: Anaplastic thyroid cancer (ATC) is an aggressive cancer that leads to rapid death if left untreated. However, recent advances in ATC treatment have dramatically changed the prognosis in a select group of patients with BRAFV600E mutations. In these patients, BRAF/MEK inhibitors have been shown to dramatically and rapidly shrink tumors. Yet, these responses are short-lived unless additional treatment modalities are applied. In patients without a BRAFV600E mutation, the current available therapies are far less effective. Summary: In this article, we review the relevant literature and propose applying the "Total Therapy" approach used since the 1960s for another deadly but curable disease, acute lymphocytic leukemia, to ATC. We have adapted the concepts of Induction, Consolidation, and Maintenance, applying them to ATC. This regimen integrates the treatments we have found to be successful in ATC: combination systemic therapy using targeted therapy plus immunotherapy, surgery, radiation, and continuation of the systemic therapy for several years, thereby attempting to eradicate all residual ATC cells. Conclusions: There has been a renewed interest in understanding the genomics of ATC and treating these patients with urgency rather than just providing palliative care. This shift has led to significant improvements in the prognosis of ATC. With the right tools and a clear roadmap to guide us, we now aim to take on the challenge of curing these patients.
    Keywords:  BRAF mutation; PDL1; RAS mutation; chemotherapy; immunotherapy; radiation
    DOI:  https://doi.org/10.1089/thy.2025.0044
  15. Cancer Metab. 2025 May 19. 13(1): 23
    S-adenosylmethionine metabolism shapes CD8+ T cell functions in colorectal cancer.
    Xiaohua Yang, Tianzhang Kou, Hongmiao Wang, Ji Zhu, Zheng-Jiang Zhu, Yuping Cai.
      Metabolite nutrients within the tumor microenvironment shape both tumor progression and immune cell functionality. It remains elusive how the metabolic interaction between T cells and tumor cells results in different anti-cancer immunotherapeutic responses. Here, we use untargeted metabolomics to investigate the metabolic heterogeneity in patients with colorectal cancer (CRC). Our analysis reveals enhanced S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism in microsatellite stable (MSS) CRC, a subtype known for its resistance to immunotherapy. Functional studies reveal that SAM and SAH enhance the initial activation and effector functions of CD8+ T cells. Instead, cancer cells outcompete CD8+ T cells for SAM and SAH availability to impair T cell survival. In vivo, SAM supplementation promotes T cell proliferation and reduces exhaustion of the tumor-infiltrating CD8+ T cells, thus suppressing tumor growth in tumor-bearing mice. This study uncovers the metabolic crosstalk between T cells and tumor cells, which drives the development of tumors resistant to immunotherapy.
    Keywords:  CD8+ T cell function; Metabolite nutrients; Metabolomics; Microsatellite stable colorectal cancer; S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolism
    DOI:  https://doi.org/10.1186/s40170-025-00394-2
  16. Bio Protoc. 2025 May 05. 15(9): e5307
    Standardized Flow Cytometry Method for Absolute Counting of Intraepithelial Lymphocytes in the Intestinal Mucosa Using TruCountTM Beads.
    Corentin Joulain, Stéphanie Bessoles, Andrada S Chiron, Guillaume Sarrabayrouse, Salima Hacein-Bey-Abina.
      In the intestinal epithelium, intraepithelial lymphocytes (IELs) coexist with intestinal epithelial cells (IECs). The IELs have an important role in defending the intestinal tract against pathogens and eliminating tumor cells. Anomalies in the absolute IEL count have been reported in various digestive diseases. IELs are typically counted using histologic techniques or under light microscopy after isolation of the epithelium. However, these techniques can introduce bias, which might account for the discrepancies in counts from one study to another. Here, we describe a flow cytometry assay for determining the absolute IEL count and the IEL/IEC ratio. We combined a conventional epithelial isolation method with a BD TruCountTM bead-based absolute counting technique to quantify IELs (CD45+ CD326/EpCAM- CD103+CD3+) and IECs (CD45- CD326/EpCAM+) in a C57BL/6 mouse model. Key features • Intraepithelial lymphocytes (IELs) play a crucial role in maintaining mucosal integrity and defending against pathogens. • Conventional manual counting of IELs using a hemocytometer relies heavily on the operator's expertise. • Flow cytometry offers a more standardized approach to cell counting. • Using TruCountTM beads to quantify IELs and intraepithelial cells (IECs) by flow cytometry and assess their ratio ensures reproducibility and comparison with immunohistochemical methods. Graphical Overview.
    Keywords:  Absolute cell count; Flow cytometry; Intestinal epithelial cells; Intraepithelial lymphocytes; Standardization; TruCountTM
    DOI:  https://doi.org/10.21769/BioProtoc.5307
  17. Cancer Immunol Res. 2025 May 19.
    TCR-based therapy directed against kallikrein-related peptidase 4 is safe and effective against prostate cancer.
    Rosa A van Amerongen, Sander Tuit, Dennis F G Remst, Anne K Wouters, Sterre L Siekman, Renate S Hagedoorn, Dirk M van der Steen, Michel G D Kester, Arnoud H de Ru, Geertje van der Horst, Masashi Matsuda, Fumihiko Ishikawa, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk.
      The efficacy of most immunotherapies for prostate cancer is limited by poor tumor immunogenicity, evidenced by minimal T-cell infiltration. Treatment with T cells engineered to express T-cell receptors (TCR) targeting prostate-specific antigens offers a potential solution by bypassing endogenous T-cell repertoire limitations. Through differential gene expression analysis, we have identified kallikrein-related peptidases 2, 3 and 4 (KLK2, KLK3, KLK4) and homeobox B13 (HOXB13) as strictly prostate lineage-specific genes with high expression in prostate cancer and no expression in healthy tissues of risk. Naturally processed peptides derived from these antigens were identified, enabling T-cell enrichment using peptide-MHC multimers. High-avidity T cells targeting these antigens were isolated from allogeneic HLA-mismatched donors. After screening for on-target tumor specificity and absence of off-target reactivity, TCRs recognizing KLK4 in HLA-A*02:01 and KLK3 in HLA-B*35:01 were sequenced and further tested. TCRs were expressed in T cells through TCR gene transfer and TCRs with best performance were selected. Using combinatorial peptide library scanning, the cross-reactive potential of the KLK4-A2 and KLK3-B35 TCRs was analyzed. The KLK3-B35 TCR exhibited cross-reactivity against two additional peptides derived from LOXHD1 and CDH23, with broad tissue-expression, and was therefore excluded. The KLK4-A2 TCR was highly specific for the KLK4 peptide. Further testing confirmed effective cytotoxic killing potential of KLK4-A2 TCR in vitro and in vivo, underscoring its therapeutic potential. These findings highlight the promise of the KLK4-A2 TCR for prostate cancer immunotherapy and demonstrate that prostate-specific antigens can be effectively targeted using TCR-gene transfer strategies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0119
  18. Immunology. 2025 May 19.
    Beyond Canonical Immune Checkpoints: Overexpression of TNFRSF Members 4-1BB and OX-40 Marks T Cells Exhibiting Phenotypic Features of Exhaustion in Cervical Carcinoma.
    Jose Manuel Rojas-Diaz, Fabiola Solorzano-Ibarra, Nadia Tatiana Garcia-Barrientos, Ksenia Klimov-Kravtchenko, Jose Alfonso Cruz-Ramos, Marcela Sofia Guitron-Aviña, Pedro Ivan Urciaga-Gutierrez, Pablo Cesar Ortiz-Lazareno, Martha Cecilia Tellez-Bañuelos, Miriam Ruth Bueno-Topete, Jesse Haramati, Susana Del Toro-Arreola.
      T cells are pivotal in combating cancer; however, they can become exhausted during tumour progression, losing their cytotoxic capacity and upregulating inhibitory receptors including PD-1 and TIGIT. While checkpoint blockade has emerged as a potent treatment option for numerous cancers, patient selection, long-term efficacy, and adverse effects still remain an issue. For these reasons, it is important to investigate other pathways that might lead to selective reactivation of the immune system. Co-stimulatory TNFRSF receptors, including 4-1BB and OX-40, have emerged as promising targets for reactivating exhausted T cells. However, their expression on exhausted peripheral and tumour-infiltrating lymphocytes (TILs) is not well characterised, particularly in cervical cancer (CC), which remains the leading cause of gynaecological cancer mortality in low- and middle-income countries. To investigate the expression of these receptors, PBMCs were collected from CC patients and healthy donors, along with TILs from tumour biopsies, and analysed using multiparametric flow cytometry. Our findings revealed an increased population of phenotypically exhausted (PD-1+TIGIT+) CD4+ and CD8+ T cells in TILs, and, to a lesser extent, in peripheral blood and from CC patients. These exhausted T cell subsets exhibited selective overexpression of 4-1BB and OX-40 compared to phenotypically non-exhausted cells (PD-1-TIGIT-). In TILs, 4-1BB was overexpressed 12.7-fold in CD8 cells with the exhausted phenotype, OX-40 was overexpressed 3.3-fold; in CD4 cells with the exhausted phenotype, the overexpression was 7.8× and 3.8× for 4-1BB and OX-40, respectively. CD8 and CD4 T cells that were PD-1 + TIGIT+ 4-1BB+ were 7.3× and 16× more likely to be found in the tumour versus peripheral blood. Additionally, subpopulations of PD-1high T cells were significantly elevated in the tumour-infiltrating T cells and TIGIT expression was positively associated with PD-1 levels in peripheral patient CD8+ and CD4+ T cells, potentially indicating an advanced state of exhaustion. These findings suggest that TNFRSF members, especially 4-1BB, may serve as potential immunotherapeutic targets for reinvigorating exhausted T cells in CC.
    Keywords:  4‐1BB; CD4+ T cell; CD8+ T cell; OX‐40; PD‐1; TIGIT; cervical cancer
    DOI:  https://doi.org/10.1111/imm.13945
  19. Nat Nanotechnol. 2025 May 21.
    Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.
    Xueting Pan, Zhihang Wang, Mixiao Tan, Ziying Fu, Guangjun Nie, Hai Wang.
      Cancer immunotherapy utilizing cytotoxic T lymphocytes has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondrial content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumour therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T cell therapy, CAR-T cell therapy and tumour-vaccine-based immunotherapy.
    DOI:  https://doi.org/10.1038/s41565-025-01909-0
  20. Front Immunol. 2025 ;16 1615030
    Editorial: Enhancing T cell function: innovations in cancer immunotherapy.
    Ji Zhang, Qihao Zhao, Qian Sun, Hong Jiang, Valentyn Oksenych, Xuefeng Wang.
      
    Keywords:  CD8 + T cells; car-t; editorial: enhancing t cell function: innovations in cancer immunotherapy cancer immunotherapy; enhancing T cell function; stem-like CD8 + T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1615030
This page is being maintained by Thomas Krichel. It was last updated on 2025‒05‒25 at 7:36.