bims-tuinly 2025-02-02 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2025–02–02
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Reverse-engineering the FLT3-PI3K/AKT axis to enhance TILs function and improve prognosis in ovarian and cervical cancers.
Tumor-Infiltrating Lymphocytes Assessed Using the International TILs Working Group System Are Not Prognostic in Medullary Thyroid Cancer.
Tumor-Infiltrating Lymphocytes and Neutrophils and Their Location in Canine Mammary Neoplasms with a Solid Arrangement: A Prognostic Factor?
Investigating Tumor-Infiltrating Lymphocytes in the Microenvironment of Oral Squamous Cell Carcinoma (OSCC) and Oral Potentially Malignant Disorders (OPMDs): Can They Shift Our Perspective? A Scoping Review.
FOXP3, IL-35, and PD-L1 in intra- and peritumoral lymphocytic infiltrate of cutaneous melanomas as an important part of antitumor immunity.
Pembrolizumab added to neoadjuvant chemotherapy may improve pathological complete response in androgen-receptor positive and low tumor-infiltrating lymphocytes triple-negative breast cancer patients.
Current Landscape of Adoptive Cell Therapy and Challenge to Develop "Off-The-Shelf" Therapy for Hepatocellular Carcinoma.
Gene armoring: A way to enhance CAR-T cell function.

J Ovarian Res. 2025 Jan 25. 18(1): 14

Reverse-engineering the FLT3-PI3K/AKT axis to enhance TILs function and improve prognosis in ovarian and cervical cancers.

Feng Hao, Zhang Yan, Luo Shen, Wang Hui, Qiu Ling, Yang Xiaoyu, Jiang Hua.

   BACKGROUND: Ovarian cancers (OC) and cervical cancers (CC) have poor survival rates. Tumor-infiltrating lymphocytes (TILs) play a pivotal role in prognosis, but shared immune mechanisms remain elusive.
METHODS: We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to explore immune regulation in OC and CC, focusing on the PI3K/AKT pathway and FLT3 as key modulators. Seurat and Harmony were employed for batch correction and dimensionality reduction. FLT3 expression was mapped with spatial data from 10 × Genomics.
RESULTS: FLT3, identified as a regulator through the PI3K/AKT pathway, showed positive correlations with T cells, NK cells, and B cells. FLT3-high regions exhibited increased immune infiltration, particularly in CC, enhancing survival outcomes.
CONCLUSION: This study provides the first spatially resolved evidence of FLT3's immune-modulatory role in OC and CC, positioning it as a promising immunotherapeutic target. FLT3-targeted strategies may offer new options for patients resistant to conventional therapies.

Keywords:  Cervical cancer; FLT3; Ovarian cancer; PI3K/AKT pathway; Spatial transcriptomics; Tumor-infiltrating lymphocytes (TILs)

DOI:  https://doi.org/10.1186/s13048-025-01592-8
Thyroid. 2025 Jan 27.

Tumor-Infiltrating Lymphocytes Assessed Using the International TILs Working Group System Are Not Prognostic in Medullary Thyroid Cancer.

Alexander Papachristos, Lydia Zhou, Amy Sheen, Mark Sywak, Bruce Robinson, Roderick Clifton-Bligh, Stan Sidhu, Anthony J Gill.

  Background: Tumor-infiltrating lymphocytes (TILs) are a protective prognostic factor in several solid tumors and predict response to immune checkpoint inhibitor therapy. The prognostic impact of TILs in medullary thyroid cancer (MTC) is poorly understood. Materials and Methods: In this retrospective cohort study, we assessed the TILs profile of primary MTC tumors using the International TILs Working Group system and correlated this with clinicopathological prognostic variables, including the International Medullary Thyroid Cancer Grading System (IMTCGS) grade and survival outcomes. Results: We identified 71 patients with primary MTC tumors who were treated surgically between 1995 and 2016 at the Royal North Shore Hospital in Sydney, Australia. The median (interquartile range) duration of follow-up was 69 (90) months. Using the ITWG system, all patients with MTC had low TILs, with a median (range) of 3% (0-10%). This group was further subdivided into "very low" (0-4%) and "low" (5-10%), and on Cox regression analysis, increasing TILs were associated with increased local recurrence (log-rank p = 0.022, odds ratio [OR] 1.94 [confidence interval or CI 0.61-6.16], p = 0.26), reduced disease-specific survival (log-rank p = 0.015, OR 5.11 [CI 1.01-26.0], p = 0.049), and a trend to decreased distant metastasis-free survival (log-rank p = 0.14). When examining the association between TILs and other prognostic factors, only "high IMTCGS grade" was significantly associated with increased TILs (OR 7.29 [CI 1.21-43.90], p = 0.015). In the multivariable logistic regression analysis, there was no significant association between TILs and local recurrence or disease-specific survival. Conclusions: In our study, the prognostic value of TILs in MTC was limited. Even high-grade MTC can be considered an immune quiescent tumor, and the adverse prognostic factors associated with higher grade tumors outweigh the marginal increase in immune recognition associated with a slight increase in TILs. The low level of TILs in MTC and their lack of correlation with survival suggest that immune checkpoint inhibitor therapy may not be effective.

Keywords:  immune checkpoint inhibitor therapy; medullary thyroid cancer; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1089/thy.2024.0595
Animals (Basel). 2025 Jan 20. pii: 287. [Epub ahead of print]15(2):

Tumor-Infiltrating Lymphocytes and Neutrophils and Their Location in Canine Mammary Neoplasms with a Solid Arrangement: A Prognostic Factor?

Mayra C Flecher, Marina P Reys, Débora Balabram, Karen Y R Nakagaki, Geovanni D Cassali.

  In canine mammary neoplasms, greater inflammation is associated with higher histological grade, lymphatic invasion, and metastases. This retrospective study assessed the density of peri- and intratumoral tumor-infiltrating lymphocytes (TILs), tumor-associated neutrophils (TANs), and CD3+ and CD79+ lymphocytes in canine mammary neoplasms with a solid arrangement, and associated such data with histological types, immunophenotype, prognostic factors, cyclooxygenase-2 (Cox-2) expression and overall and cancer-specific survival. Sixty-one neoplasms with a solid arrangement were classified as malignant myoepitheliomas (6/9.8%), solid papillary carcinomas (8/13.1%), carcinomas with a solid pattern (9/14.8%), basaloid carcinomas (BC) (19/31.1%), and malignant adenomyoepitheliomas (19/31.1%). Intra- and peritumoral TILs, TANs, and TCD3+ and BCD79+ lymphocytes were counted, and based on the resulting median, the neoplasms were divided into low or high cell infiltration. BCs had the lowest density of intratumoral TILs (p = 0.02), and luminal B neoplasms showed a significantly higher density of intratumoral TCD3+ than luminal A cases. Neoplasms with a higher density of peritumoral CD3+ and CD79+ had significantly greater proliferative activity. High infiltration of intratumoral BCD79+ lymphocytes was related to nodal metastasis (p = 0.03). Intratumoral TILs and TCD3+ were associated with shorter survival time. Therefore, intratumoral lymphocyte infiltration is possibly an important feature in the progression of cancer and influences the survival in bitches with solid arrangement neoplasms.

Keywords:  CD3; CD79; dogs; mammary neoplasms; metastasis; neutrophils; survival analysis; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/ani15020287
J Clin Med. 2025 Jan 18. pii: 606. [Epub ahead of print]14(2):

Investigating Tumor-Infiltrating Lymphocytes in the Microenvironment of Oral Squamous Cell Carcinoma (OSCC) and Oral Potentially Malignant Disorders (OPMDs): Can They Shift Our Perspective? A Scoping Review.

Samuele Sutera, Olga Anna Furchì, Monica Pentenero.

  Background/Objectives: Tumor-infiltrating lymphocytes (TILs) play a crucial role in the tumor microenvironment (TME), influencing the progression, prognosis, and response to treatment in oral squamous cell carcinoma (OSCC) and its precursors, oral potentially malignant disorders (OPMDs). This scoping review assesses the current literature on TILs in the TME of OSCC and OPMDs, aiming to identify trends and gaps in the research. Methods: A comprehensive search was performed in PubMed, using the following query terms: "Tumor Microenvironment AND (mouth neoplasms OR oral lichen OR leukoplakia OR oral lichenoid OR dysplasia OR GVHD OR lupus)". Based on the inclusion criteria, we selected in vivo human original research and clinical observational studies that focused on TILs within the TME of OSCC and OPMDs. Results: Out of 1152 results in PubMed, 58 studies were selected and analyzed. These studies investigated various TILs, including T cells, B cells, and natural killer (NK) cells. Of these, 47 studies focused on the OSCC TME, 4 examined the OPMDs ME, and 7 compared OSCC TME and OPMDs ME. Discussion: While TILs in OSCC have been extensively studied, research on infiltrating lymphocytes in OPMDs is still limited. In OSCC, CD8+ T cells, T helper 1 cells, and NK cells are associated with strong antitumor activity, whereas CD4+ T cells, including T helper 2 and regulatory T cells, are linked to protumoral effects. B cells remain less explored due to their low frequency in the TME. In OPMDs, trends suggest an increase in activated CD8+ T cells in OLP and lower NK cell numbers compared to OSCC, which may contribute to malignant transformation. Understanding the spatial distribution and activation status of TILs within the TME is essential for deciphering their role. The variability in TIL composition highlights the complexity of the TME. Conclusions: Current knowledge remains preliminary, though it highlights the crucial role of TILs in carcinogenesis and OSCC. A more in-depth understanding could improve diagnostic and therapeutic strategies, including the assessment of the risk of malignant transformation in OPMDs.

Keywords:  carcinogenesis; malignant transformation; oral potentially malignant disorder; oral squamous cell carcinoma; prognostic biomarker; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/jcm14020606
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2025 Jan 22.

FOXP3, IL-35, and PD-L1 in intra- and peritumoral lymphocytic infiltrate of cutaneous melanomas as an important part of antitumor immunity.

Vladimir Zidlik, Pavel Hurnik, Yvetta Vantuchova, Simona Michalcova, Jozef Skarda, Tereza Hulinova, Dana Purova, Jiri Ehrmann.

   BACKGROUND: The tumor microenvironment is a significant mediator enabling tumor growth and progression. Tumor-infiltrating lymphocytes (TILs) are an important component of this but tumor cells develop mechanisms by which they can escape the action of the immune system. Immunosuppressive mechanisms cooperate with each other and involve cells of the immune system, the tumor microenvironment itself, chemokines and cytokines. In this study, we examined the FOXP3+, IL-35+, and PD-L1+ lymphocytes in tumor tissues as they are contributing to immunosuppression in some tumors, including melanoma. Such cells are also associated with tumor progression, early metastasis, and prognosis.
METHODS AND RESULTS: In this study, 95 cutaneous melanomas and 25 melanocytic nevi as a control group were examined by immunohistochemistry for FOXP3+, IL-35+, and PD-L1+ lymphocytes. Melanomas were divided into four groups according to the TNM classification: pT1 (35), pT2 (21), pT3 (21), and pT4 (18). PD-L1+ lymphocytes were enriched in pT3- and pT4-stage melanomas, especially in the periphery of the lesions (P<0.001). The number of FOXP3+ lymphocytes was positively correlated with the stage of the disease, especially in the center of the tumors (P<0.001). Likewise, IL-35+ lymphocytes (P<0.001) were enriched with the stage of the tumor.
CONCLUSION: This article demonstrates that the immunosuppressive environment develops in proportion to the stage of the melanoma. The most significant changes are found at the tumor periphery, confirming the heterogeneity of the tumor stroma which is more pronounced in more advanced tumors and which may contribute to the greater aggressiveness in these peripheral zones.

Keywords:  cutaneous melanoma; immune checkpoints; immunosuppression; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.5507/bp.2024.040
Breast Cancer. 2025 Jan 29.

Pembrolizumab added to neoadjuvant chemotherapy may improve pathological complete response in androgen-receptor positive and low tumor-infiltrating lymphocytes triple-negative breast cancer patients.

Kadri Altundag.

DOI: https://doi.org/10.1007/s12282-025-01672-z
J Gastroenterol Hepatol. 2025 Jan 26.

Current Landscape of Adoptive Cell Therapy and Challenge to Develop "Off-The-Shelf" Therapy for Hepatocellular Carcinoma.

Seung Kak Shin, Yuta Mishima, Yoonseok Lee, Oh Sang Kwon, Ju Hyun Kim, Yun Soo Kim, Shin Kaneko.

  Adoptive cell therapy (ACT) is a type of immunotherapy in which autologous or allogeneic immune cells, such as tumor-infiltrating lymphocytes or engineered lymphocytes, are infused into patients with cancer to eliminate malignant cells. Recently, autologous T cells modified to express a chimeric antigen receptor (CAR) targeting CD19 showed a positive response in clinical studies for hematologic malignancies and have begun to be used in clinical practice. This article discusses the current status and promise of ACT research in hepatocellular carcinoma (HCC), focusing on challenges in off-the-shelf ACT using primary cells or induced pluripotent stem cells (iPSCs) with or without genetic engineering. Early clinical trials of autologous GPC-3-, MUC1-, or CEA-targeted CAR-T cell therapies are underway for HCC. There is a growing demand for the development of off-the-shelf therapies due to the high cost and manufacturing issues associated with autologous CAR-T. The development of ACT from various cell sources, such as NK cells, NKT cells, macrophages, and γδ T cells without MHC restriction other than T cells has been proposed. Advances in genome editing, including HLA gene knockout to avoid GvHD, and strategies to enhance efficacy in overcoming the suppressive tumor microenvironment, are used to create universal 'off-the-shelf' CAR-T cells which can be used immediately as therapeutic products from healthy donors or iPSC-derived immune cells. Despite several limitations, cell-based immunotherapy is expected to become a key cancer treatment modality for both hematologic malignancies and solid tumors including HCC, thanks to technological advancements overcoming these challenges.

Keywords:  adoptive cell therapy; hepatocellular carcinoma; immunotherapy; off‐the‐shelf

DOI:  https://doi.org/10.1111/jgh.16872
Pharmacol Res. 2025 Jan 25. pii: S1043-6618(25)00047-7. [Epub ahead of print] 107622

Gene armoring: A way to enhance CAR-T cell function.

Yuxin Chen, Lulu Han, Ying Cai, Shuxin Huang, Meng Wang, Huizhong Li, Junnian Zheng, Bo Ma, Gang Wang.



Keywords:  CAR-T; Immunotherapy; Solid tumors

DOI:  https://doi.org/10.1016/j.phrs.2025.107622