bims-tuinly Biomed News
on Tumor-infiltrating lymphocytes therapy
Issue of 2025–04–27
eleven papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Tumor-infiltrating lymphocytes as predictive biomarkers in neoadjuvant treatment of HER2-positive breast cancer.
  2. Histopathological biomarkers in squamous cell carcinoma of the vulva: the prognostic relevance of tumor-infiltrating lymphocytes (TILs)-a retrospective study of 157 cases.
  3. The Tumor Immune Environment: Advances in the Cancer Immunotherapy Era.
  4. Promising New Anti-TIGIT Agents: Stealthy Allies in Cancer Immunotherapy.
  5. NEDDylation regulates CD8+ T cell metabolism and anti-tumor immunity.
  6. Unveiling the Landscape of PD-L1 Expression and Tumor-Infiltrating Lymphocyte Subtypes in Advanced Triple-Negative Breast Cancer in Brazil.
  7. Overcoming antigen loss in CAR T therapy with Vγ9Vδ2 CAR T-cells.
  8. Acquired resistance to immunotherapy in solid tumors.
  9. An antibody targeting an immune checkpoint molecule BTN2A2 enhances anti-tumor immunity.
  10. Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.
  11. Ex vivo pre-activation shifts the in vivo differentiation of adoptively transferred CD8+ T cells in a melanoma model.
  1. Oncologist. 2025 Apr 04. pii: oyaf054. [Epub ahead of print]30(4):
    Tumor-infiltrating lymphocytes as predictive biomarkers in neoadjuvant treatment of HER2-positive breast cancer.
    Oğuzcan Kınıkoğlu, Yunus Emre Altıntaş, Anıl Yıldız, Goncagül Akdağ, Hamit Bal, Zeynep Yüksel Yaşar, Uğur Özkerim, Hacer Şahika Yıldız, Sıla Öksüz, Salih Tünbekici, Akif Doğan, Deniz Işık, Alper Yaşar, Tuğba Başoğlu, Heves Sürmeli, Hatice Odabaş, Nedim Turan.
       BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have emerged as predictive biomarkers in HER2-positive breast cancer, correlating with treatment response and survival outcomes. This study evaluates the impact of TIL levels and Ki67 suppression on neoadjuvant therapy efficacy in this patient population.
    MATERIALS AND METHODS: A retrospective analysis of 136 HER2-positive breast cancer patients was conducted. Patients were stratified by TIL levels, and clinical outcomes, including Ki67 expression, pathological complete response (pCR), and disease-free survival (DFS), were assessed.
    RESULTS: High TIL levels (≥ 40%) were significantly associated with higher pCR rates (60.32% vs. 39.73%, P = .02) and with TIL ≥ 10% greater Ki67 suppression. In patients with low TIL levels, high Ki67 expression correlated with better pCR rates (57.1% vs 30.8%, P = 0.010), while in high TIL patients, no significant difference was observed between high and low Ki67 groups (P = 0.317). A trend toward improved DFS was noted in the high TIL group, with 3-year survival rates of 91.9% vs. 80.7% in the low TIL group, though this was not statistically significant (P = .062).
    CONCLUSION: TIL levels are robust predictors of pCR and Ki67 suppression in HER2-positive breast cancer, particularly in patients with high initial TILs. These findings highlight the potential for integrating TIL evaluation into personalized treatment strategies to optimize neoadjuvant therapy outcomes. Further research is warranted to validate these results and explore underlying mechanisms.
    Keywords:  HER2-positive breast cancer; Ki67 suppression; neoadjuvant therapy; pathological complete response; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.1093/oncolo/oyaf054
  2. Discov Oncol. 2025 Apr 19. 16(1): 572
    Histopathological biomarkers in squamous cell carcinoma of the vulva: the prognostic relevance of tumor-infiltrating lymphocytes (TILs)-a retrospective study of 157 cases.
    Gilbert Georg Klamminger, Meletios P Nigdelis, Yaman Degirmenci, Bashar Haj Hamoud, Erich Franz Solomayer, Laura Schnöder, Bernd Holleczek, Marcus Schmidt, Annette Hasenburg, Mathias Wagner.
       BACKGROUND: The prognostic relevance of tumor-infiltrating lymphocytes (TILs) has so far been recognized in several solid tumors like in breast, endometrial and ovarian cancer-nonetheless, the immune contexture of squamous cell carcinomas of the vulva, analyzed by means of stromal (s) and intratumoral (i) TILs, remains yet to be elucidated.
    MATERIAL AND METHODS: In this study, we examined the immunooncological biomarkers sTILs and iTILs in 157 vulvectomy specimens with histologically diagnosed vulvar squamous cell carcinoma (VSCC) according to the standardized methodology proposed by the International Immunooncology Biomarkers Working Group in 2017. In a next step, we evaluated the association of infiltrating lymphocytes to traditional histopathological parameters such as infiltration depth and HPV related tumorigenesis. After determining optimal cut-off values using Receiver Operating Characteristic (ROC) curve analysis, we assessed the prognostic relevance of sTILs and iTILs with regard to overall survival, local recurrence, and metastasis using the Log-rank (Mantel-Cox) test and Fisher's exact test.
    RESULTS: We propose optimal cut-off values of 5% for iTILs and 20% for sTILs analysis, which identify patients with a distinct superior survival rate (sTILs: p = 0.0137; iTILs: p = 0.0226). Furthermore, a low number of iTILs was associated with a higher risk of local recurrence in our study collective (p = 0.0432).
    CONCLUSION: The fast and cost-effective determination of the histological biomarkers iTILs and sTILs yields prognostic relevance in vulvar cancer. A potential integration within the routine diagnostic workflow could be globally feasible, even in resource-poor settings.
    Keywords:  Histological biomarker; Immunooncological biomarker; TILs; Tumor-infiltrating lymphocytes; Vulvar cancer
    DOI:  https://doi.org/10.1007/s12672-025-02381-x
  3. Methods Mol Biol. 2025 ;2926 15-34
    The Tumor Immune Environment: Advances in the Cancer Immunotherapy Era.
    Adit Ben-Baruch.
      For over the last hundred years, the scientific community has demonstrated much interest in the roles of the immune system in regulating tumor progression. Extensive research that was performed in this context has revealed that mechanisms of acquired immunity can be highly potent in eradicating cancer cells, if given the right conditions to do so. Basic and clinical studies have paved the way toward the design of sophisticated modalities that improve the ability of T cells to efficiently recognize cancer antigens (when expressed by the tumor cells) and to expand thereafter; alongside developing procedures that prevent immune suppression caused by inhibitory immune checkpoints, these approaches offer cancer patients improved immunotherapies, which increase remission and prolong survival. The current chapter provides a summary of key aspects relevant to such immunotherapies, including the following: (1) cancer vaccines that enhance cancer antigen presentation; (2) adoptive cell transfer (ACT)-based therapies, like tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor expressing T cells (CAR-T cells); and (3) immune checkpoint blockades (ICBs) that downregulate the extent of immune suppression mediated by inhibitory immune checkpoint molecules, like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligands, primarily PD-L1 (and also PD-L2). These treatments have revolutionized the immunotherapy field, demonstrating the strong power of acquired immunity in preventing tumor growth and progression, giving much hope to cancer patients worldwide.
    Keywords:  Adoptive cell therapy; Cancer vaccines; Chimeric antigen receptor T cells; Immune checkpoint blockades; Immune surveillance; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/978-1-0716-4542-0_2
  4. Clin Transl Sci. 2025 Apr;18(4): e70212
    Promising New Anti-TIGIT Agents: Stealthy Allies in Cancer Immunotherapy.
    Gatadi Srikanth, Durga Prasad Beda, Ashish Ranjan Dwivedi, Nandan Kumar Duddukuri, Srinivas Nanduri, Jitendra Patel.
      TIGIT (T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain), Vstm3, and VSIG9, are newly recognized immunological checkpoints. They are prominently expressed on CD4+ and CD8+ T cells, tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, and regulatory T cells (Tregs). The TIGIT (TIGIT) protein is crucial for immune modulation since it diminishes NK cell populations and hinders T cell activity in cancer patients and experimental models. CD155, the principal ligand of TIGIT in humans, has been recognized as a pivotal target for immunotherapy owing to its interaction with TIGIT. CD155 is linked to the efficacy of anti-programmed cell death protein 1 (PD-1) therapy, even without TIGIT expression, underscoring its importance in immune checkpoint suppression. Anti-TIGIT medicines, either independently or in conjunction with anti-PD-1 treatments, have demonstrated potential in augmenting immune responses to malignancies. This review examines the structural and functional characteristics of the TIGIT protein, new developments in anti-TIGIT drugs, and their prospective use in cancer immunotherapy.
    Keywords:  PD‐1; TIGIT; cancer; immunotherapy; resistance
    DOI:  https://doi.org/10.1111/cts.70212
  5. Cancer Immunol Res. 2025 Apr 22.
    NEDDylation regulates CD8+ T cell metabolism and anti-tumor immunity.
    Borja Jimenez-Lasheras, Paloma Velasco-Beltrán, Leire Egia-Mendikute, Lorena Pérez-Gutiérrez, So Young Lee, Ander de Blas, Ana García Del Río, Samanta Romina Zanetti, Asier Antoñana-Vildosola, Adrián Barreira-Manrique, Alexandre Bosch, Jone Etxaniz Díaz de Durana, Endika Prieto-Fernández, Marina Serrano-Maciá, Naroa Goikoetxea-Usandizaga, Mikel Azkargorta, Felix Elortza, Thomas Gruber, Sebastian Peer, Gottfried Baier, Ashwin Woodhoo, María Luz Martínez-Chantar, Asis Palazon.
      NEDDylation is a post-translational modification whereby the ubiquitin-like molecule NEDD8 is attached to protein substrates in a process dependent on NEDD8 activating enzyme regulatory subunit (NAE1). NEDDylation is emerging as a regulator of cancer biology, but its precise role in antitumor immunity has not been thoroughly characterized. Here, we study the impact of NEDDylation in CD8+ T cell-mediated antitumor responses. Analysis of publicly available single-cell RNA sequencing databases revealed that CD8+ tumor-infiltrating lymphocytes (TILs) showed increased expression of NEDD8 during their differentiation into effector memory cells. In vitro activation of mouse and human CD8+ T cells drove the upregulation of the NEDDylation enzymatic pathway, resulting in an enrichment of NEDDylated proteins. In vivo tumor challenge assays demonstrated that CD8+ T cells lacking NAE1 (NAE1-KO) exhibited reduced antitumor capability and a less activated phenotype with compromised differentiation into effector cells. Upregulating NEDDylation by knocking out deNEDDylase sentrin-specific protease 8 (SENP8) increased the in vitro cytotoxic capability of CD8+ CAR T cells. In addition, LC MS/MS proteomic analyses of NAE1-KO CD8+ T cells and CD8+ T cells treated with the NEDDylation inhibitor MLN4924, showed a pronounced impairment in metabolic pathways, including glycolysis and oxidative phosphorylation. In this context, we validated lactate dehydrogenase A, α-enolase and hexokinase 1, which are relevant glycolytic enzymes, as NEDD8 targets. In line with this, NEDDylation-deficient CD8+ T cells demonstrated reduced transcription, protein expression and enzymatic activity of lactate dehydrogenase. In summary, we uncover NEDDylation as a critical regulator of CD8+ T cell-mediated antitumor immunity.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0127
  6. Breast Cancer (Dove Med Press). 2025 ;17 349-358
    Unveiling the Landscape of PD-L1 Expression and Tumor-Infiltrating Lymphocyte Subtypes in Advanced Triple-Negative Breast Cancer in Brazil.
    Alexssandra Lima Siqueira Dos Santos, Jesse Lopes Da Silva, Lucas Zanetti De Albuquerque, Antônio Lucas Araújo Neto, Cecília Ferreira Da Silva, Luana Aguiar Mesquita Cerva, Isabele Avila Small, Fabiana Resende Rodrigues, Fabiane Carvalho De Macedo, Cicera Pimenta Marcelino, Paula de Mendonça Batista, Maria Aparecida do Carmo Rego, Maria Amélia Carlos Souto Maior Borba, Andreia Cristina De Melo.
       Purpose: This study aimed to assess the frequency and prognostic significance of programmed cell death ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) subtypes in advanced triple-negative breast cancer (TNBC).
    Patients and Methods: A database search was conducted to identify women with previously untreated locally recurrent inoperable or metastatic TNBC treated between January 2018 and December 2022. The inclusion criteria required formalin-fixed paraffin-embedded samples aged less than four years. PD-L1 expression was evaluated using the PD-L1 IHC 22C3 pharmDx assay, and the combined positive score (CPS) was calculated. TIL subtypes were assessed using immunohistochemical staining.
    Results: The study included 150 patients, with a median age of 51.5 years. The majority of patients were younger than 65 years, postmenopausal, non-white, and had metastatic TNBC. CPS≥10 was observed in 20.9% of cases, mainly in postmenopausal women. No significant differences were found in demographic characteristics and clinicopathological variables across PD-L1 subgroups. Tumors with PD-L1 CPS≥10 had higher expression of CD3+, CD4+, and CD8+ TIL subtypes. Most patients received first-line chemotherapy, with smaller proportions undergoing second, third, and fourth-line treatments. No statistically significant differences were observed in median progression-free survival (PFS) or overall survival (OS) across PD-L1 subgroups in this cohort of chemotherapy-treated patients.
    Conclusion: This study provides insights into the expression profiles of PD-L1 and TIL subtypes in advanced TNBC. The PD-L1 CPS status did not significantly affect survival outcomes, but variations in TIL subtype composition were observed based on PD-L1 CPS status.
    Keywords:  PD-L1 expression; immunohistochemistry; molecular epidemiology; progression-free survival; triple-negative breast cancer; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.2147/BCTT.S499373
  7. Immunooncol Technol. 2025 Jun;26 101053
    Overcoming antigen loss in CAR T therapy with Vγ9Vδ2 CAR T-cells.
    M Velasco Santiago, P Aehnlich, T M Hulen, K M Jensen, G Holmen Olofsson, Ö Met, P Thor Straten.
       Background: Vγ9Vδ2 T-cells demonstrate potent antitumor activity in vitro but, despite successful safety studies, the clinical benefit of Vγ9Vδ2 in adoptive cell therapy has been limited. One approach to enhance the therapeutic potential of Vγ9Vδ2 T-cells while maintaining their safety profile is genetic engineering to express a chimeric antigen receptor (CAR). Vγ9Vδ2 CAR T-cells retain the ability to target tumor cells even after target antigen loss, a major cause of CAR treatment relapse.
    Methods: Vγ9Vδ2 T-cells were expanded from peripheral blood mononuclear cells in the presence of high levels of interleukin 2 (IL-2) or IL-2 in combination with IL-15. Cells were then virally transduced with a CD19-directed CAR and underwent antigen-specific stimulation to enrich CAR-expressing cells.
    Results: Vγ9Vδ2 CAR T-cells showed similar cytotoxic activity to conventional αβ-CAR T-cells against CD19-positive tumor cells. They demonstrated superior responses against CD19-negative tumor cells, however, particularly when IL-15 was included during expansion. This enhanced function was further confirmed in co-culture assays with mixed CD19-positive and CD19-negative tumor populations, simulating antigen loss.
    Conclusions: Vγ9Vδ2 CAR T-cell therapy presents a promising strategy for B-cell malignancies, offering sustained antitumor activity even after antigen loss. This approach may help overcome a major limitation of conventional CAR T-cell therapy, potentially improving clinical outcomes.
    Keywords:  B-cell malignancies; CAR T-cells; Vγ9Vδ2 T-cells; antigen loss
    DOI:  https://doi.org/10.1016/j.iotech.2025.101053
  8. Trends Mol Med. 2025 Apr 23. pii: S1471-4914(25)00061-9. [Epub ahead of print]
    Acquired resistance to immunotherapy in solid tumors.
    Perrine Verdys, Astrid Z Johansen, Anurag Gupta, Mario Presti, Edoardo Dionisio, Daniel H Madsen, Alessandra Curioni-Fontecedro, Marco Donia.
      Acquired resistance to immunotherapy (ARI) is a major challenge in solid tumors, limiting long-term success in up to 65% of patients who initially respond to immunotherapy. Defining ARI clinically remains complex, but ongoing efforts aim to establish standardized criteria. This review describes recent insights into ARI, revealing complex mechanisms involving both tumor-intrinsic mechanisms - such as antigen loss and presentation defects, interferon γ (IFNγ) insensitivity, tumor-mediated T cell exclusion, and metabolic reprogramming - as well as extrinsic factors such as inhibitory molecule upregulation, immunosuppressive cells, extracellular matrix (ECM) remodeling, and dysbiotic microbiota. Understanding the development of ARI is crucial for prevention and effective interventions. The integration of innovative strategies and translational research on appropriately collected samples is key to overcoming ARI and ensuring durable benefits for patients.
    Keywords:  ICI; acquired resistance; immunotherapies; solid tumors
    DOI:  https://doi.org/10.1016/j.molmed.2025.03.010
  9. Neoplasia. 2025 Apr 21. pii: S1476-5586(25)00040-5. [Epub ahead of print]65 101161
    An antibody targeting an immune checkpoint molecule BTN2A2 enhances anti-tumor immunity.
    Li Xiao, Rong Hu, Wei Chen, Jie Gao, Youbo Zhao, Zuli Wang, Guangshi Du, Yishen Tian, Laijun Lai, Lu Liu, Min Su.
      Tumors exploit immune checkpoints to evade immune responses. Therefore, targeting these checkpoints has become a key strategy in cancer immunotherapy. In this study, we have developed a novel immune checkpoint inhibitor (ICI) targeting the B7 family-related molecule BTN2A2. The human BTN2A2 protein, which was highly expressed in some tumor tissues and activated antigen-presenting cells (APCs), can inhibit T cell activation and proliferation. The anti-BTN2A2 monoclonal antibody (mAb) can neutralize the inhibitory effect of BTN2A2 on T cells. In mouse models of pancreatic cancer and glioma, compared to the control group, the anti-BTN2A2 treatment group exhibited tumor shrinkage of 35.8 % (P < 0.05) and 51.2 % (P < 0.01), respectively, along with increased CD8+ tumor-infiltrating lymphocytes (TILs) by 1.7-fold (P < 0.001) and 2.2-fold (P < 0.001), respectively. In addition, anti-BTN2A2 mAb also increased the infiltration of B cells, M1 macrophages, and the expression of inflammatory cytokines in T cells, while reducing the infiltration of M2 macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). Thus, anti-hBTN2A2 mAb normalizes the immunodeficient tumor microenvironment (TME) and inhibits tumor growth. Our results suggest that targeting the BTN2A2 immune checkpoint may represent a novel strategy for cancer treatment, especially in immunosuppressive 'cold' tumors.
    Keywords:  B7 family; BTN2A2; Immune checkpoint inhibitor (ICI); T cells; Tumor immunity; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.neo.2025.101161
  10. Front Immunol. 2025 ;16 1548509
    Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.
    Agathe Dubuisson, Adèle Mangelinck, Samantha Knockaert, Adrien Zichi, Etienne Becht, Wendy Philippon, Sandra Dromaint-Catesson, Manon Fasquel, Fabien Melchiore, Nicolas Provost, Dawid Walas, Hélène Darville, Jean-Pierre Galizzi, Céline Lefebvre, Véronique Blanc, Vincent Lombardi.
       Background: The ability of immune cells to rapidly respond to pathogens or malignant cells is tightly linked to metabolic pathways. In cancer, the tumor microenvironment (TME) represents a complex system with a strong metabolism stress, in part due to glucose shortage, which limits proper T cell activation, differentiation and functions preventing anti-tumor immunity.
    Methods: In this study, we evaluated T cell immune reactivity in glucose-restricted mixed lymphocyte reaction (MLR), using a comprehensive profiling of soluble factors, multiparametric flow cytometry and single cell RNA sequencing (scRNA-seq).
    Results: We determined that glucose restriction potentiates anti-PD-1 immune responses and identified thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake, as a potential immunometabolic modulator of T cell activation. We confirmed TXNIP downregulation in tumor infiltrating T cells in cancer patients. We next investigated the implication of TXNIP in modulating immune effector functions in primary human T cells and showed that TXNIP depletion increased IFN-γ secretion and tumor cell killing.
    Conclusions: TXNIP is at the interface between immunometabolism and T cell activation and could represent a potential target for immuno-oncology treatments.
    Keywords:  T cells activation; TXNIP; cancer immunotherapy; glucose deprivation; mixed lymphocyte reaction; single-cell RNA-sequencing; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1548509
  11. Mol Immunol. 2025 Apr 22. pii: S0161-5890(25)00104-X. [Epub ahead of print]182 139-149
    Ex vivo pre-activation shifts the in vivo differentiation of adoptively transferred CD8+ T cells in a melanoma model.
    Jinjin Lu, Jianjun Hu, Ziyao Zhao, Xiuming Zhai, Cheng Chen, Xinyu Zheng, Yanping Yang, Yuhao Zheng, Lilin Ye, Qin Tian, Yifei Wang.
      Adoptive transfer of TCR-specific CD8+ T cells represents a powerful experimental platform for investigating tumor-specific CD8+ T cell responses within the framework of anti-tumor immunity. Genetic modulation of these transferred cells provides a robust strategy to elucidate the intrinsic molecular mechanisms underlying T cell differentiation and functionality, thereby offering critical insights to optimize tumor-specific CD8+ T cell antitumor immunity in cancer immunotherapy. A key aspect of this approach is the ex vivo activation of primary T cells, which raises important questions regarding the impact of pre-activation on subsequent T cell differentiation. In this study, we explored the differentiation trajectories of pre-activated CD8+ T cells and performed a comprehensive characterization of their epigenetic and transcriptional profiles using a murine melanoma model. Our findings revealed that ex vivo pre-activation not only attenuates progression towards terminal exhaustion in the tumor-draining lymph nodes (TdLNs) but also enhances the stem-like characteristics of CD8+ T cells within the tumor microenvironment (TME). Leveraging comprehensive ATAC-seq and RNA-seq analyses, we demonstrated that pre-activation modulates the epigenetic landscape and transcriptional profile of CD8+ T cells, fostering effector-related differentiation in the TdLNs while promoting stemness-associated programming in the TME. These findings highlight the profound influence of ex vivo pre-activation on the differentiation pathways of tumor-specific CD8+ T cells, underscoring the necessity of taking these experimental framework-induced discrepancies into consideration for more accurate data interpretation in relevant researches.
    Keywords:  Epigenetic and transcriptional profiling; Exhausted T cell; Stem-like exhausted T cell; T cell pre-activation; Tumor-specific CD8(+) T cell
    DOI:  https://doi.org/10.1016/j.molimm.2025.04.007
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