bims-tuinly 2025-10-19 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–10–19
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Assessment of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Interobserver Variability and Contributing Factors.
Facts and Hopes for Neoantigen-Enriched TIL.
Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells.
Artificial Intelligence-Detected Tumor-Infiltrating Lymphocytes and Outcomes in Anti-PD-1-Based Treated Melanoma.
Tumor-Infiltrating Lymphocytes Predict Extranodal Extension and Prognosis in Regionally Advanced Oral Cavity Cancer.
The paradoxical prognostic effects of T-cell-derived circulating DNA in EGFR-mutated advanced non-small-cell lung cancer involve the crosstalk between heme biosynthesis and immune microenvironment.
Comparative analysis of PD-L1 expression and tumor-infiltrating lymphocytes between primary breast cancer and matched metastatic lesions: implications for immunotherapy.
Long-Acting Recombinant IL-7 (rhIL-7-hyFc) Enhances the Primary and Memory Neoantigen-Specific Immune Response to Breast Cancer Personalized Cancer Vaccines.
Enhanced Collagen Prolyl 4-Hydroxylase Activity and Expression Promote Cancer Progression via Both Canonical and Non-Canonical Mechanisms.
Interaction between tumor-infiltrating lymphocytes and BMI in early HER2-positive breast cancer: analysis of the ShortHER trial.
Exacerbation of demyelinating polyneuropathy after adoptive cell therapy with tumour-infiltrating lymphocytes by metastatic melanoma.
Infiltration characteristics and regulatory mechanisms of CD8+ T lymphocytes in solid tumors: spatial distribution, biological functions, and interactions with the immune microenvironment.

Diagnostics (Basel). 2025 Sep 30. pii: 2492. [Epub ahead of print]15(19):

Assessment of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Interobserver Variability and Contributing Factors.

Nurkhairul Bariyah Baharun, Mohamed Afiq Hidayat Zailani, Afzan Adam, Qiaoyi Xu, Muaatamarulain Mustangin, Reena Rahayu Md Zin.

  Background/Objectives: Tumor-infiltrating lymphocytes (TILs) are emerging as a crucial prognostic biomarker in triple-negative breast cancer (TNBC). However, their clinical utility remains constrained by the subjectivity and interobserver variability of manual scoring, despite standardization efforts by the International TILs Working Group (TIL-WG). This study aimed to evaluate the interobserver agreement among pathologists in scoring stromal and intratumoral TILs from H&E-stained TNBC slides and to identify contributing histological factors. Methods: Two consultant pathologists at Hospital Canselor Tuanku Muhriz, Kuala Lumpur, independently assessed 64 TNBC cases using TIL-WG guidelines. Interobserver agreement was quantified using the intraclass correlation coefficient (ICC) and Cohen's kappa coefficient. Cases with over 10% scoring discrepancies underwent review by a third pathologist, and a consensus discussion was held to explore the underlying confounders. Results: Our results showed moderate interobserver agreement for stromal TILs (ICC = 0.58) and strong agreement for intratumoral TILs (ICC = 0.71). Significant variability was attributed to three main confounding variables: heterogeneous TIL distribution, poorly defined tumor-stroma interface, and focal dense lymphoid infiltrates. Conclusions: These findings highlight the need for standardized TIL scoring protocols and suggest that validated AI-based tools may help mitigate observer variability in future TIL assessments.

Keywords:  diagnostic reproducibility; interobserver variability; intraclass correlation; manual TIL scoring; triple-negative breast cancer (TNBC); tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.3390/diagnostics15192492
Clin Cancer Res. 2025 Oct 15.

Facts and Hopes for Neoantigen-Enriched TIL.

Siqi C Brough, Kristen L Skonieczny, Stav Leibou, Frank J Lowery, Stephanie L Goff.

After decades of development, adoptive transfer of tumor infiltrating lymphocytes (TIL immunotherapy) was approved by the US FDA for patients with checkpoint-refractory metastatic melanoma in 2024. Application of the strategy to more common epithelial cancers has depended on the translation of key findings about tumor and T cell interactions derived from studies of patients with melanoma. Central to that effort has been the identification of neoantigens and neoantigen-reactive TIL. Using laboratory techniques to guide the selection of TIL has mediated modest tumor regression, but new strategies to enrich TIL remain in development in the hopes of improving clinical efficacy in the treatment of solid tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4146
Cancer Immunol Res. 2025 Oct 13.

Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell-fate decisions by neoantigen-specific CD8+ T cells.

Ying Luo, Taidou Hu, Chen Yao, Tuoqi Wu.

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell-fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and T-cell receptor (TCR) profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes (TILs) upregulated gene signatures of T-cell activation and exhaustion compared to those recognizing other tumor antigens. In the tumor-draining lymph node, we identified TCF1+TOX- TSCM, TCF1+TOX+ TPEX, and TCF1-TOX+ effector-like TEX subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared to clones biased towards TEX, TPEX, or TSCM. The TPEX subset had greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into TEX TILs. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph-node residence predicted a poorer response to immune checkpoint inhibitors by cancer patients. In conclusion, we have identified a transcriptional program that controls the cell-fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in cancer patients.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0203
JAMA Oncol. 2025 Oct 16.

Artificial Intelligence-Detected Tumor-Infiltrating Lymphocytes and Outcomes in Anti-PD-1-Based Treated Melanoma.

Mark Schuiveling, Isabella A J van Duin, Laurens S Ter Maat, Janneke C van der Weerd, Rik J Verheijden, Franchette van den Berkmortel, Christian U Blank, Gerben E Breimer, Femke H Burgers, Marye Boers-Sonderen, Alfons J M van den Eertwegh, Jan Willem B de Groot, John B A G Haanen, Geke A P Hospers, Ellen Kapiteijn, Djura Piersma, Gerard Vreugdenhil, Hans Westgeest, Anne M R Schrader, Josien P W Pluim, Paul J van Diest, Mitko Veta, Karijn P M Suijkerbuijk, Willeke A M Blokx.

Importance: Easy and accessible biomarkers associated with response to immune checkpoint inhibition (ICI)-treated melanoma are limited.
Objective: To evaluate artificial intelligence (AI)-detected tumor-infiltrating lymphocytes (TILs) on pretreatment melanoma metastases as a biomarker for response and survival in patients treated with ICIs.
Design, Setting, and Participants: This multicenter cohort study included patients with advanced melanoma treated with first-line anti-programmed cell death 1 protein (PD-1) with or without anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) between January 2016 and January 2023 at 11 melanoma treatment centers in the Netherlands. Data were analyzed from January to July 2025.
Exposure: All patients received first-line anti-PD-1 with or without anti-CTLA-4.
Main Outcomes and Measures: The percentage of TILs inside manually annotated tumor area in hematoxylin-eosin-stained pretreatment metastases was determined using the Hover-NeXt model trained and evaluated on an independent melanoma dataset containing 161 835 pathologist-verified manually annotated cells. The primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). Correlation with manual TILs, scored according to the guidelines stated by the Immuno-Oncology Biomarkers Working Group, was evaluated with Spearman correlation coefficients. Logistic regression and Cox proportional regression were conducted, adjusted for age, sex, disease stage, ICI type, BRAF status, brain metastases, lactate dehydrogenase level, and performance status.
Results: Of 1202 included patients with advanced cutaneous melanoma, 445 (37.0%) were female and 757 (63.0%) were male, and the median (IQR) age was 67.0 (57.0-74.0) years. The median follow-up was 36.3 months (95% CI, 34.0-39.1). Metastatic melanoma specimens were available for 1202 patients, of whom 423 received combination therapy. The median (range) TIL percentage was 9.9% (0.3%-69.4%). A 10% increase in TILs was associated with increased ORR (adjusted odds ratio, 1.40; 95% CI, 1.23-1.59), PFS (adjusted hazard ratio, 0.85; 95% CI, 0.79-0.92), and OS (adjusted hazard ratio, 0.83; 95% CI, 0.76-0.91). Results were consistent for both patients treated with anti-PD-1 monotherapy and patients treated with combination treatment with anti-PD-1 plus anti-CTLA-4. When comparing manual TIL scoring with AI-detected TILs, associations with response and survival were consistently stronger for AI-detected TILs.
Conclusions and Relevance: In this cohort study, among patients with advanced melanoma, higher levels of AI-detected TILs on pretreatment hematoxylin-eosin slides were independently associated with improved ICI response and survival. Given the accessibility of TIL scoring on routine histology, TILs may serve as a biomarker for ICI outcomes. To facilitate broader validation, the Hover-NeXt architecture and model weights are publicly available.

DOI: https://doi.org/10.1001/jamaoncol.2025.4072
Diagnostics (Basel). 2025 Sep 24. pii: 2431. [Epub ahead of print]15(19):

Tumor-Infiltrating Lymphocytes Predict Extranodal Extension and Prognosis in Regionally Advanced Oral Cavity Cancer.

Mia Lorencin Bulic, Martin Jurlina, Danko Müller, Lada Lijovic, Matija Mamic, Ivica Luksic.

  Background/Objectives: Oral cavity squamous cell carcinoma (OCSCC) is an aggressive malignancy, often diagnosed at an advanced stage and with stagnant survival outcomes despite advances in surgical and oncologic management. Tumor-infiltrating lymphocytes (TILs) have been explored as potential prognostic markers in many solid tumors; however, their role in OCSCC remains under researched. This study aimed to assess the prognostic value of TILs in a cohort of patients with regionally advanced, p16-negative squamous cell carcinoma of all oral cavity subsites and to evaluate for any correlation of TILs and extranodal extension (ENE). Methods: A retrospective study was conducted on 103 consecutive patients treated with comprehensive surgical resection. TILs were quantified using the standardized method proposed by the International Immuno-Oncology Biomarkers Working Group. Statistical analyses evaluated associations with a comprehensive set of independent variables and survival endpoints. Results: High stromal infiltration at the invasive margin (>25%) was independently associated with significantly improved overall survival (HR 4.53, p = 0.005), disease-specific survival (HR 4.49, p = 0.008), and disease-free survival (HR 3.42, p = 0.025). Patients with ENE demonstrated lower TILs compared with ENE-negative patients (median 40% vs. 57.5%), a difference that reached statistical significance in both parametric and nonparametric testing (Welch's t-test p = 0.032; Mann-Whitney U p = 0.030). Conclusions: TILs quantified by this standardized method are a reliable, independent prognostic biomarker in regionally advanced OCSCC of all subsites and are also associated with extranodal extension of regional metases. This study gives rationale for consideration of inclusion of TILS into future immunotherapeutic decision-making and further investigations of TIL-ENE association.

Keywords:  extranodal extension; oral cavity squamous cell carcinoma; prognostic factor; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/diagnostics15192431
Sci Rep. 2025 Oct 17. 15(1): 36434

The paradoxical prognostic effects of T-cell-derived circulating DNA in EGFR-mutated advanced non-small-cell lung cancer involve the crosstalk between heme biosynthesis and immune microenvironment.

Nicha Zungsontiporn, Chaiyapong Ngamchokwathana, Sakun Santisukwongchote, Piyada Sitthideatphaiboon, Nophol Leelayuwatanakul, Krittiya Korphaisarn, Poonchavist Chantranuwat, Virote Sriuranpong, Chatchawit Aporntewan, Nattiya Hirankarn, Chanida Vinayanuwattikun.

  The paradoxical impact of T-cell-derived circulating DNA (T-cirDNA) and prognostication in advanced non-small cell lung cancer (NSCLC) has been reported. Further exploration was conducted in 158 EGFR-mutated NSCLC participants who received EGFR inhibitors, correlated with tumor PD-L1 score, CD8 tumor-infiltrating lymphocytes (TILs), and bulk RNA sequencing. We categorized T-cirDNA levels into three groups based on a previous study: undetectable (26.8%), low (≤ 1% ratio; 36.6%), and high (> 1% ratio; 36.6%). Undetectable and high T-cirDNA groups were independent factors correlated with favorable outcomes. The presence of intra-tumoral CD8 TILs (≥ 1%) was also an independent unfavorable prognostic factor; however, it had the lowest proportion in the low T-cirDNA group (16%). Tumor-immune microenvironment (TIME)-related gene set enrichment analysis revealed an overlapped significant heme biosynthesis signature correlated with poor outcome and diverse T-cirDNA group. Despite a high heme biosynthesis signature score in the undetectable T-cirDNA group, inverse correlation with CIBERSORT-activated CD4 memory T-cells was found (R - 0.79, p-value 0.019). Those findings were contrary to the low and high T-cirDNA groups. The significant contribution of heme biosynthesis was the overexpression of CPOX. Crosstalk of EGFR and COPX function prohibits the activation of CD4 + memory T-cells or the spatial intra-tumoral CD8 + T-cells. Undetectable T-cirDNA represents inactivated naïve T-cells and solely active downstream EGFR signaling.

Keywords:  EGFR tyrosine kinase inhibitor; Non-small cell lung cancer; T-cell-derived circulating DNA; Tumor microenvironment

DOI:  https://doi.org/10.1038/s41598-025-20307-z
Cent Eur J Immunol. 2025 ;50(2): 135-148

Comparative analysis of PD-L1 expression and tumor-infiltrating lymphocytes between primary breast cancer and matched metastatic lesions: implications for immunotherapy.

Daolin Zeng, Qin Li, Xia Wang, Le Xiong, QiongYu Lan, Hanjie Yi.

   Introduction: The PD-1/PD-L1 immune checkpoint pathway plays a critical role in tumor immune escape and disease progression. This study investigated differences in tumor-infiltrating lymphocytes (TILs) and PD-L1 expression between primary breast cancers and matched metastatic lesions, and their relationships with clinical outcomes.
Material and methods: We retrospectively analyzed 54 female breast cancer patients who underwent radical mastectomy between May 2011 and December 2018 at the Second Affiliated Hospital of Nanchang University and later developed recurrent disease. Immunohistochemical (IHC) analysis was performed on matched primary and metastatic tumor samples to evaluate TILs and PD-L1 expression patterns. Associations between these immune parameters and clinical characteristics were assessed.
Results: IHC analysis of 50 paired primary and metastatic lesions revealed distinct PD-L1+ TIL expression patterns across different molecular subtypes of breast cancer. Patients with PD-L1+ tumors showed significantly shorter median disease-free survival (DFS) and overall survival (OS) compared to those with PD-L1- tumors. We observed significant differences in the immune microenvironment between primary and metastatic sites, with metastatic lesions showing consistently lower TIL density, PD-L1+ TIL density, and tumor PD-L1 expression compared to matched primary tumors.
Conclusions: Our findings demonstrate systematic differences in immune parameters between primary and metastatic breast cancer sites, with reduced immune infiltration in metastatic lesions. The data suggest that targeting the PD-1/PD-L1 pathway may be particularly beneficial in patients with PD-L1+ TIL-high primary tumors, potentially by reinvigorating anti-tumor immune responses.

Keywords:  PD-L1; breast cancer; immune microenvironment; postoperative recurrence

DOI:  https://doi.org/10.5114/ceji.2025.149541
Cancers (Basel). 2025 Sep 30. pii: 3177. [Epub ahead of print]17(19):

Long-Acting Recombinant IL-7 (rhIL-7-hyFc) Enhances the Primary and Memory Neoantigen-Specific Immune Response to Breast Cancer Personalized Cancer Vaccines.

Michael Chen, Thomas Kane, Ina Chen, Suangson Supabphol, Xiuli Zhang, Alexandra A Wolfarth, Donghoon Choi, Lijin Li, S Peter Goedegebuure, William E Gillanders.

  Background: Personalized cancer vaccines (PCVs) are a promising form of cancer immunotherapy, capable of eliciting robust neoantigen-specific immune responses. However, cancer neoantigens are variable in terms of immunogenicity, and PCVs may be less effective when targeting weak neoantigens. Strong and durable immune responses are also likely to be critical for vaccine efficacy. Interleukin-7 (IL-7) is a common gamma-chain cytokine known to support T cell development and survival, and a long-acting form of recombinant human IL-7 fused with hybrid Fc (rhIL-7-hyFc) has shown potential to enhance immune responses in early-stage clinical trials. Methods: In this study, we evaluated the ability of rhIL-7-hyFc to serve as a molecular adjuvant to a DNA PCV in the E0771 murine breast cancer model. Results: We found that the combination of rhIL-7-hyFc and DNA PCV treatment prolonged neoantigen-specific CD8+ T cell responses, improved functional memory as measured based on in vivo cytotoxicity, and increased the number of neoantigen-specific tumor-infiltrating lymphocytes (TILs), resulting in improved prophylactic tumor protection and durable memory responses. Conclusions: Our findings support the potential of rhIL-7-hyFc to enhance the efficacy of PCVs and suggest clinical utility for adjuvant rhIL-7-hyFc in cancer immunotherapy.

Keywords:  DNA vaccine; breast cancer; immune response; neoantigen; recombinant IL-7

DOI:  https://doi.org/10.3390/cancers17193177
Int J Mol Sci. 2025 Sep 25. pii: 9371. [Epub ahead of print]26(19):

Enhanced Collagen Prolyl 4-Hydroxylase Activity and Expression Promote Cancer Progression via Both Canonical and Non-Canonical Mechanisms.

Dalton Hironaka, Gaofeng Xiong.

  Collagens make up the main components of the extracellular matrix (ECM), and, in cancer, are often aberrantly secreted by both tumor cells and stromal cells in the tumor microenvironment (TME). Collagen prolyl 4-hydroxylase (C-P4H), an enzyme that hydroxylates proline into 4-hydroxyproline at the Y position of the collagen -X-Y-Gly- triplet motif, is essential for the stability of the mature collagen trimer and collagen secretion. In this review, we summarize the research on the structure and function of C-P4H, the regulation of C-P4H enzyme activity, and the role of overexpression of its α-subunit, P4HA1, in promoting cancer progression as well as its potential as a prognostic marker and therapeutic target. Overexpression of P4HA1 is displayed in almost all solid cancers, including breast, colorectal, and lung cancer, and is associated with cancer progression, worse response to therapy, and poorer patient survival. Characterization of P4HA1 overexpression has demonstrated links to key hallmarks of cancer, not only in the canonical collagen deposition role, but also in non-canonical functions, such as cell stemness, hypoxic response, glucose metabolism, angiogenesis, and modulation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. P4HA1 is thus an attractive target for developing novel targeted therapies to improve treatment response in many cancer types.

Keywords:  collagen; prolyl 4-hydroxylase; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26199371
ESMO Open. 2025 Oct 10. pii: S2059-7029(25)01701-6. [Epub ahead of print]10(11): 105832

Interaction between tumor-infiltrating lymphocytes and BMI in early HER2-positive breast cancer: analysis of the ShortHER trial.

M V Dieci, G Bisagni, S Bartolini, L Cavanna, A Musolino, F Giotta, A Rimanti, O Garrone, E Bertone, K Cagossi, S Sarti, A Ferro, F Piacentini, E Orvieto, M Sanders, F Miglietta, S Balduzzi, R D'Amico, P Conte, V Guarneri.

   BACKGROUND: We demonstrated the prognostic role of tumor-infiltrating lymphocytes (TILs) in patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer (eBC) enrolled in the ShortHER trial. Here, we analyze how body mass index (BMI) modulates the prognostic role of TILs.
PATIENTS AND METHODS: The ShortHER study randomized 1253 patients with HER2-positive eBC to 9 weeks versus 1 year of adjuvant trastuzumab + chemotherapy. We assessed BMI at diagnosis (available for n = 1213, n = 34 underweight were excluded). Survival endpoints were disease-free survival (DFS), recurrence-free survival (RFS), distant DFS (DDFS) and overall survival (OS). We calculated the cumulative incidence of first event types by competing risk analysis.
RESULTS: A total of 583 (48%) patients were lean, 360 (29.7%) overweight and 236 (19.5%) obese. Lean patients versus those with overweight or obesity had similar DFS, RFS, DDFS and OS. Within the TIL + BMI cohort (n = 819), TILs (5% increase) were independently associated with DFS (P = 0.003), RFS (P = 0.001) and DDFS (P = 0.018) in lean patients. In patients with overweight or obesity, TILs were independently associated only with DDFS (P = 0.044). In lean patients, TILs ≥20% were associated with improved DFS (P = 0.007), RFS (P = 0.002) and DDFS (P = 0.027) compared with TILs <20%. In patients with overweight or obesity, DFS, RFS, DDFS and OS did not significantly differ between TILs ≥20% and TILs <20%. In lean patients, there was a higher cumulative incidence of locoregional relapse (P = 0.001) and distant relapse (P = 0.07) in patients with TILs <20% versus TILs ≥20%. In patients with overweight or obesity, there was a higher cumulative incidence of distant relapse (P = 0.005) in patients with TILs <20% versus TILs ≥20%.
CONCLUSIONS: We suggest that BMI may impair the local, but not distant, protective effect of TILs in patients with overweight or obesity with HER2-positive eBC treated with adjuvant chemotherapy + trastuzumab.

Keywords:  BMI; HER2-positive; TILs; breast cancer

DOI:  https://doi.org/10.1016/j.esmoop.2025.105832
Swiss Med Wkly. 2025 Aug 21. 155 4221

Exacerbation of demyelinating polyneuropathy after adoptive cell therapy with tumour-infiltrating lymphocytes by metastatic melanoma.

Elisa Canini, Lorenza Pacchin, Ann Kristine Blackham, Johannes Lorscheider, Jakob Passweg, Alfred Zippelius, Heinz Läubli, Markus R Mutke, David König.

Adoptive cell therapy (ACT) with tumour-infiltrating lymphocytes (TIL) is an effective personalised immunotherapy for patients with advanced pretreated melanoma. For TIL-ACT, tumour-specific T cells are expanded from excised tumour samples and stimulated in cell culture with interleukin-2 (IL-2). The resulting autologous tumour-infiltrating lymphocytes are reinfused to the patient after a non-myeloablative lymphodepleting chemotherapy with cyclophosphamide and fludarabine. Thereafter, activation of tumour-infiltrating lymphocytes in the patient is supported by the administration of high-dose IL-2. Although effective, there is a need for enhancement of TIL-ACT in terms of effectiveness and toxicity. Most of the toxicity in this multistep, complex treatment regimen is due to the preparative chemotherapy and high-dose IL-2 treatment. At University Hospital Basel, we are currently evaluating an experimental approach of TIL-ACT in which we replace high-dose IL-2 by in vivo tumour-infiltrating lymphocyte activation with ANV419, a novel antibody-cytokine fusion protein consisting of IL-2 fused to an anti-IL-2 monoclonal antibody, in an ongoing phase I trial (BaseTIL-03M). The primary endpoint of the study is safety. We herein describe the case of a patient included in the BaseTIL-03M trial with chronic inflammatory demyelinating polyneuropathy who received TIL-ACT with ANV419 and developed an acute polyneuropathy of Guillain-Barré syndrome.

DOI: https://doi.org/10.57187/s.4221
Front Immunol. 2025 ;16 1661545

Infiltration characteristics and regulatory mechanisms of CD8+ T lymphocytes in solid tumors: spatial distribution, biological functions, and interactions with the immune microenvironment.

Peng Ouyang, Jianhong Zhang, Xiao He, Congcong Yang, Dingcheng Zeng, Daofeng Xu.

  CD8+ T lymphocytes are central effectors of anticancer immunity. Their abundance and spatial distribution within solid tumors are strongly correlated with patient prognosis and response to immune-checkpoint inhibitors (ICIs). Tumors have been categorized into "hot," "excluded," and "cold" types based on the infiltration patterns of CD8+ T cells, which reflect the underlying immune contexture and therapeutic potential. However, many tumors remain resistant to T-cell infiltration, posing a significant barrier to immunotherapy. This review systematically outlines the seven critical steps of the Cancer-Immunity Cycle that govern CD8+ T-cell infiltration: antigen release, antigen processing and presentation, T-cell priming, trafficking through the vasculature, tumor infiltration, target recognition, and cytolytic activity. At each step, tumor-intrinsic and microenvironmental barriers-including low tumor mutational burden, defective antigen-presenting machinery, immunosuppressive cytokines (e.g., TGF-β, IL-10), abnormal vasculature, fibroblast-derived extracellular matrix, and inhibitory cell populations (e.g., Tregs, MDSCs, TAMs)-can stall the immune response. We further discuss the roles of immune-checkpoint signaling, metabolic competition, and suppressive cell networks in shaping T-cell exhaustion and exclusion. Cutting-edge technologies-such as single-cell RNA-sequencing, spatial transcriptomics, imaging mass cytometry, and TCR repertoire profiling-have revealed spatial and functional heterogeneity within intratumoral CD8+ T cells and informed the design of rational combination therapies. Understanding and targeting these barriers is critical for converting immune-cold tumors into immune-infiltrated, therapy-responsive states. We conclude with a perspective on the future of immunoengineering and immune-atlas integration to optimize CD8+ T-cell-based interventions in solid tumors.

Keywords:  CD8+ T cells; T-cell infiltration; cancer-immunity cycle; immunotherapy resistance; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1661545