bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–05–11
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Tumor-infiltrating CD8+ T-cell numbers and serum C-reactive protein levels as a prognostic biomarker in hepatocellular carcinoma patients receiving atezolizumab plus bevacizumab.
  2. Relationship between tumor infiltrating lymphocytes and hormone-sensitive (breast and prostate) cancer survival: cases received at Yaoundé General Hospital (Cameroon) from 2019 to 2023.
  3. Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy.
  4. Characterizing the immune landscape of tumor-infiltrating lymphocytes in non-small cell lung cancer.
  5. Prognostic Role of Tumor-Infiltrating Lymphocytes, Tumor Budding, Tumor Border Configuration, and Tumor Stroma Ratio in Colorectal Carcinoma.
  6. Reduced dose fludarabine and cyclophosphamide lymphodepletion before tumor-infiltrating lymphocyte therapy in melanoma.
  7. Prognostic impact of tumor-infiltrating lymphocytes in HER2+ metastatic breast cancer receiving first-line treatment.
  8. Effective TIL therapy for patients with checkpoint-resistant melanoma without lymphodepleting regimens requires interferon-alpha.
  9. Biomarkers of response to antibody-drug conjugates (TROP2 and nectin-4) and the immune microenvironment (NKG7, PD-L1, and B7-H3) in penile squamous cell carcinoma.
  1. Hepatol Res. 2025 Apr;55(4): 600-610
    Tumor-infiltrating CD8+ T-cell numbers and serum C-reactive protein levels as a prognostic biomarker in hepatocellular carcinoma patients receiving atezolizumab plus bevacizumab.
    Akifumi Kuwano, Masayoshi Yada, Kosuke Tanaka, Junro Takahira, Hideo Suzuki, Yoshihiro Ohishi, Kenta Motomura.
       AIM: Atezolizumab plus bevacizumab is an established first-line treatment for unresectable hepatocellular carcinoma (HCC). Our previous research identified CD8+ tumor-infiltrating lymphocytes (TILs) as a potential biomarker for predicting patient response to this therapy. However, not all HCC patients with CD8+ TILs respond favorably to atezolizumab and bevacizumab. Moreover, elevated serum C-reactive protein (CRP) levels have been associated with poor outcomes in patients treated with immune checkpoint inhibitors across various cancer types. The aim of this study was to determine whether CD8+ TIL numbers combined with serum CRP levels could collectively predict the response to atezolizumab and bevacizumab better than CD8+ TIL numbers alone.
    METHODS: A total of 46 HCC patients who provided liver biopsy samples were included. CD8+ TIL numbers in liver tissue were measured using immunohistochemistry.
    RESULTS: A group of 13 patients (28.3%) with high CD8+ TIL numbers and low (≤0.54 mg/dl) serum CRP levels demonstrated the highest treatment response rate. Furthermore, this group had a significantly longer median overall survival and progression-free survival than the remaining 33 patients. Multivariate analysis revealed that high CD8+ TIL numbers with low CRP levels (HR 0.264; p = 0.037) and Child-Pugh class A (HR 0.277; p = 0.009) were associated with improved overall survival.
    CONCLUSIONS: These findings suggest that the combination of CD8+ TIL numbers and serum CRP levels may serve as a useful biomarker for predicting the efficacy of atezolizumab plus bevacizumab in HCC patients.
    Keywords:  CD8+ T cells; C‐reactive protein; atezolizumab plus bevacizumab; hepatocellular carcinoma; tumor‐infiltrating lymphocytes
    DOI:  https://doi.org/10.1111/hepr.14157
  2. Pan Afr Med J. 2025 ;50 78
    Relationship between tumor infiltrating lymphocytes and hormone-sensitive (breast and prostate) cancer survival: cases received at Yaoundé General Hospital (Cameroon) from 2019 to 2023.
    Stéphane Zingue, Etienne Okobalemba Atenguena, Kevine Ghubap Makamte, Danielle Ingrid Tekam Maliedje, Laure Leka Zingue, Manuella Mayemi, Estelle Alida Ngne Mbopda, Zacharie Sando.
       Introduction: cancer ranks as the second leading cause of mortality worldwide, manifesting in diverse forms and impacting various tissues, notably prostate cancer (PCa) in men and breast cancer (BCa) in women. Cancer is a malignant tumor that can induce an immune response. During this reaction, immune cells are produced which are responsible for ridding the body of senescent and/or tumor cells, and constitute tumor effectors. Studies have shown that the presence of tumor-infiltrating lymphocytes (TILs) is a good prognostic marker for assessing survival in cancer patients; however, no similar data have yet been published in Cameroon.
    Methods: the aim of this study was to investigate the relationship between TILs and the survival of breast and prostate cancer patients at Yaoundé General Hospital (YGH) between 2019 and 2023. For this, a retrospective and cross-sectional study was undertaken at the Oncology Department and the Anatomo-Cytopathology Laboratory of YGH. A consecutive non-probability sampling (from August to October 2023) of 212 breast cancer patients and 89 prostate cancer patients who agreed to participate in the study constituted our sample. Variables were survival, TILs, sociodemographic, clinical, and pathological characteristics of patients. The TILs were estimated after Hematoxylin-Eosin (HE) staining and staged as low, middle and high TILs rate. The variables were sociodemographic characteristics (age, education level, religion, marital status, ethnolinguistic area, and menopause); clinical characteristics (affected breast, histological type, histological grade, type of treatment, AJCC stage, consistency of discovery); different grades of TILs. Furthermore, the correlation between TILs and chemotherapy as well as TILs and survival were analyzed. The obtained data were analyzed using Microsoft Excel, Epi-info 7 and SPSS software and statistical significance was considered at p< 0.05. Furthermore, the Cox regression analysis to identify factors associated with survival was performed.
    Results: the mean age was 43.56 ± 11.90 years for BCa with stage II and SBR grade II being the most common with proportions of 48.34% and 54.72%, respectively (n= 212). While in PCa, the mean age was 75 to 84 years (34.83%, n= 89) with stage II being the most frequent. Microscopic analysis of breast tissues revealed four TILs grades: absent (17.45%), low (18.40%), intermediate (27.83%) and high TIL grade (36.32%), while in PCa the most represented TILs grade was intermediate (31.46%). In BCa the intermediate TILs grade was positively associated with a good response to chemotherapy (p< 0.05). The overall 5-year survival in this study was around 44% for BCa, whereas it was 42 months for those with infiltration in PCa. No positive correlation was found between TILs grade and survival in BCa patients (p= 0.45), while in PCa, it was found that TILs are significantly correlated (p =0.016) with survival. Patients with prostate cancer who had not taken treatment had a 7.23 greater risk of death (HR: 7.23, 95% CI 1.21-53.14; p= 0.049) than those who had.
    Conclusion: no positive association was observed between TILs as graded and 5-year survival in BCa patients; however, it may have prognostic value in PCa patients. Further studies are encouraged to investigate the association between BCa molecular groups and TILs.
    Keywords:  Tumor-infiltrating lymphocytes; breast cancer; hormone-dependent cancer; prostate cancer
    DOI:  https://doi.org/10.11604/pamj.2025.50.78.43588
  3. Nat Cancer. 2025 May 08.
    Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy.
    Chao Wang, Xiaoqing Yu, Jamie K Teer, Jiqiang Yao, Dongliang Du, Xiaoxian Liu, Zachary J Thompson, Min Hsuan Wang, Eric A Welsh, Danish Memon, Timothy A Chan, Vladimir Makarov, Carmen M Anadon, Lamees Saeed, Theresa A Boyle, Bin Fang, John M Koomen, Cheryl Cox, Ana M Landin, Sean J Yoder, Sungjune Kim, Dung-Tsa Chen, Shari A Pilon-Thomas, Jose R Conejo-Garcia, Scott J Antonia, Eric B Haura, Benjamin C Creelan.
      Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
    DOI:  https://doi.org/10.1038/s43018-025-00946-x
  4. Genes Immun. 2025 May 05.
    Characterizing the immune landscape of tumor-infiltrating lymphocytes in non-small cell lung cancer.
    Jin-Guo Liu, Lin Yu, Xian-Ling Guo, Xue-Min He, Man Li, Ren-Yuan Gao, Bing-Hui Zhao, Qian-Yu Li, Wen-Jing Zhu, Ping Xu, Xiao-Hua Gu, Yong-An Chen, Xiao-Lan Yin, Yan Shang, Zhen-Hong Guo, Jia-Hao Mao, Yang-Xi Hu, Li-Ming Lu, Jian Hua, Hua Zhang, Yue Li.
      Tumor-Infiltrating Lymphocytes (TILs) immunotherapy is a highly promising treatment for Non-small Cell Lung Cancer (NSCLC), which is responsible for 18% of all cancer-related deaths. The heterogeneity of TILs remains poorly understood. Here, we utilized combined single-cell RNA (scRNA)/T cell receptor sequencing (scTCR-seq) data from lung adenocarcinoma (LUAD) patients. Naïve CD4+ and effector memory CD8+ T cells were increased in tumor tissue compared with circulating blood samples. Activated signaling pathways were detected, and GZMA was identified as a potential novel diagnostic biomarker. During the transitional phase, macrophages (FTL) and dendritic (AIF1) cells transported the most CD3 TCR clones to T cells, while cytotoxicity CD8+ T (NKG7) cells transported to terminal exhausted CD8+ T cells. In both transition and expansion phases, T helper cells (CXCL13) are transported to regulatory T cells (Tregs). Additionally, we investigated the expression profiles of key cytokines, checkpoint receptors, and their ligands. Cytotoxicity CD8+ T cells (CCL5 and IFNG), T helper cells (FTL, TNFRSF4, and TIGIT), and regulatory T cells (CTLA4, TIGIT and FTL) exhibited functional roles in both primary and metastatic tumor stages. Taken together, our study provides a single-cell resolution of the TIL immune landscape and suggests potential treatment strategies to overcome drug resistance.
    DOI:  https://doi.org/10.1038/s41435-025-00330-w
  5. Indian J Surg Oncol. 2025 Apr;16(2): 691-697
    Prognostic Role of Tumor-Infiltrating Lymphocytes, Tumor Budding, Tumor Border Configuration, and Tumor Stroma Ratio in Colorectal Carcinoma.
    Mukta Pujani, Kanika Singh, Charu Agarwal, Varsha Chauhan, Sneha Prasad, Mitasha Singh, Ruchira Wadhwa, Alka Yadav.
      Histomorphological features like tumor-infiltrating lymphocytes (TIL), tumor budding (TB), tumor stroma ratio (TSR), and tumor border configuration (TBC) may provide important prognostic information for more accurate stratification and personalized therapeutic approach in colorectal cancer (CRC). The objective of the current study was to investigate the prognostic impact of novel histopathological features (TIL, TB, TBC, TSR) and a new combined risk score (CRS) in primary CRC. This cross-sectional observational study was conducted on hematoxylin and eosin (H&E)-stained slides of 65 primary CRC cases. Stromal TIL was categorized into 3 groups: low (0 to 10%), intermediate (15 to 50%), and high (55 to 100%). Tumor budding was counted in 10 HPFs and graded as follows: 0-4 buds-low TB, 5-9 buds-intermediate TB, and 10 or more buds-high TB. TBC was labeled as either pushing or infiltrative. TSR was scored into two groups as high TSR (low stroma as ≤ 50%) and low TSR (high stroma > 50%). A novel CRS was constructed based on TBC, TB, and TSR: Infiltrating TBC, TB score > 5 (median), and low TSR were categorized as risk items. Final categories were as follows: low-risk tumors with ≤ 1 risk item and high-risk tumors with > 1 risk items. TIL showed a significant correlation with histological tumor type; TB was significantly associated with tumor location, grade, T stage, and perineural invasion, while TBC significantly correlated with tumor location only. TSR showed significant association with tumor location and perineural invasion, while the combined risk score significantly correlated with tumor location and grade. Tumor border configuration, tumor budding, tumor stroma ratio, and the newly formed combined risk score are simple, cost-effective, potential markers in colorectal cancer patients, suggesting that their incorporation in the routine histopathological evaluation could be useful in determining the prognosis of colorectal cancer cases.
    Keywords:  Colorectal carcinoma; Tumor border configuration; Tumor budding; Tumor stroma ratio; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s13193-024-02127-1
  6. Future Oncol. 2025 May 09. 1-7
    Reduced dose fludarabine and cyclophosphamide lymphodepletion before tumor-infiltrating lymphocyte therapy in melanoma.
    Muhammad Umair Mushtaq, Haitham Abdelhakim, Luke Selby, Moazzam Shahzad, Sunil H Abhyankar, Joseph P McGuirk, Gary C Doolittle.
       CLINICAL TRIAL REGISTRATION: NCT06151847.
    Keywords:  Tumor-infiltrating lymphocytes; clinical trial protocol; immunotherapy; lymphodepletion chemotherapy; metastatic melanoma
    DOI:  https://doi.org/10.1080/14796694.2025.2498842
  7. NPJ Breast Cancer. 2025 May 10. 11(1): 41
    Prognostic impact of tumor-infiltrating lymphocytes in HER2+ metastatic breast cancer receiving first-line treatment.
    Beatrice Taurelli Salimbeni, Fabiola Giudici, Carlo Pescia, Pier Paolo Maria Berton Giachetti, Roberta Scafetta, Paola Zagami, Antonio Marra, Dario Trapani, Angela Esposito, Simone Scagnoli, Bruna Cerbelli, Andrea Botticelli, Elisabetta Munzone, Nicola Fusco, Carmen Criscitiello, Giuseppe Curigliano.
      Breast cancer (BC) is a leading cause of death among women, with approximately 30% HER2-positive (HER2+). Although HER2-targeted therapies have improved outcomes for patients with HER2+ metastatic breast cancer (mBC), clinical challenges and prognostic variability remain. Tumor-infiltrating lymphocytes (TILs) have emerged as prognostic and predictive biomarkers in various tumors, including BC, but their role in HER2+ mBC is poorly understood. This multicentric retrospective cohort study evaluated the prognostic significance of TILs in 110 patients with HER2+ mBC treated with pertuzumab, trastuzumab, and taxane-based chemotherapy at two Italian institutes from June 2013 to May 2024. TILs were assessed on metastatic or primary tumor samples. High TILs levels (>5%) were independently associated with longer PFS and OS. TILs levels were higher in primary tumours than in metastases (p = 0.009), with significant variation by metastatic site. These findings underscore the potential of TILs as prognostic biomarkers in HER2+ mBC, necessitating further prospective studies.
    DOI:  https://doi.org/10.1038/s41523-025-00760-9
  8. Clin Cancer Res. 2025 May 06.
    Effective TIL therapy for patients with checkpoint-resistant melanoma without lymphodepleting regimens requires interferon-alpha.
    Els M E Verdegaal, Anique L C Verpoorte, Monique K van der Kooij, Linda de Bruin, Marten Visser, Caroline E van der Minne, Vera Weeda, Inge C F M Roozen, Mare A Jonker, Inge M Westra, Pauline Meij, Frank M Speetjens, Stephanie M Zunder, Gerrit-Jan Liefers, Saskia J Santegoets, Sjoerd H van der Burg, Ellen H W Kapiteijn.
       PURPOSE: Melanoma patients progressing despite immune checkpoint blockade (ICB) may benefit from adoptive transfer of tumor infiltrating lymphocytes (TIL).
    PATIENTS AND METHODS: We investigated the impact of a pegylated interferon-alpha (IFNa) conditioning and support regimen on the safety and efficacy of TIL plus Nivolumab (NCT03638375). ICB-resistant stage III/IV melanoma patients were treated with TIL plus Nivolumab without (n=9) or with (n=25) IFNa.
    RESULTS: The treatment was safe, side effects include IFNa-induced lymphopenia (16%) and neutropenia (12%). No febrile neutropenia and no > grade 4 adverse events were observed. Disease control was obtained in 11.1% (95% CI: -14.5%-36.7%) of the patients treated without and in 41.7% (95% CI: 20.4%-62.9%) of the patients treated with IFNa, clearly suggesting the need for IFNa support. IFNa treatment strongly reduced the numbers of circulating leukocytes and neutrophils, more consistently in therapy responders. No differences were observed in the phenotype and dose of TIL administered.
    CONCLUSION: Taken together, our low-toxicity therapy comprising TIL, Nivolumab and IFNa is safe, shows evidence of clinical activity, and may be particularly suitable for more frail patients who are less able to tolerate lymphodepletion and high-dose interleukin-2 regimens.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-4322
  9. Am J Clin Pathol. 2025 May 06. pii: aqaf022. [Epub ahead of print]
    Biomarkers of response to antibody-drug conjugates (TROP2 and nectin-4) and the immune microenvironment (NKG7, PD-L1, and B7-H3) in penile squamous cell carcinoma.
    Burak Tekin, John C Cheville, Fabrice Lucien, Michael McCarthy, Haidong Dong, Karla J Kopp, Nate R Torell, Roxane R Lavoie, Ava Farrell, Brandy L Jaszewski, Carin Y Smith, Sarah M Jenkins, Surendra Dasari, Santosh Menon, Rumeal D Whaley, Stephen A Boorjian, Lance C Pagliaro, Lori A Erickson, Ruifeng Guo, Sounak Gupta.
       OBJECTIVES: We aimed to assess the expression of biomarkers of response to antibody-drug conjugates (TROP2 and nectin-4) and immune microenvironment (NKG7, PD-L1, and B7-H3) in penile squamous cell carcinoma (pSCC).
    METHODS: Our archive was queried for patients who had a penectomy for pSCC between 2000 and 2022. Primary tumors were immunostained for B7-H3 and NKG7, while metastatic specimens were immunostained for TROP2 and nectin-4. Expression of PD-L1, TROP2, and nectin-4 in primary tumors was previously characterized. H-scores (0-300) were used to quantify expression. Associations between biomarkers, tumor-infiltrating lymphocytes (TILs), and clinicopathologic and outcome parameters were evaluated.
    RESULTS: For both TROP2 and nectin-4, H-scores within the lymph node metastases were higher compared to those within the primary tumors (mean, 264.5 vs 244.8, P = .0003; mean, 170.6 vs 146.7, P = .05, respectively; 33 paired specimens). For B7-H3 (n = 107), 32.7% of the primary tumors had an H-score of more than 0. In 34.8% of the cases, NKG7 expression was observed in 25% to 50% of the TILs. A significant association was noted between TIL density, B7-H3, NKG7, and PD-L1 expression.
    CONCLUSIONS: Therapeutic strategies targeting TROP2 and nectin-4 hold promise for patients with advanced pSCC. The potential of PD-L1, B7-H3, and NKG7 for predicting response to immunomodulatory treatment warrants further research.
    Keywords:  B7-H3; NKG7; PD-L1; TROP2; antibody-drug conjugate; nectin-4; penis; squamous cell carcinoma; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1093/ajcp/aqaf022
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