bims-tuinly 2024-12-01 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2024–12–01
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Comment on "Dense Tumor-Infiltrating Lymphocytes (TILs) in Liver Metastasis From Colorectal Cancer Are Related to Improved Overall Survival".
The Role of Lymphocytic Infiltrates in the Tumor Microenvironment as a Predictive Factor for the Response to Immunotherapy in Solid Tumors: A Single-Center Experience From Romania.
T-cell immunotherapy for melanoma.
Advances in cell therapy: progress and challenges in hematological and solid tumors.
Tumor-Infiltrating B Cells and Tissue-Resident Memory T Cells as Prognostic Indicators in Brain Metastases Derived from Gastrointestinal Cancers.
Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Enduring Legacy, Emerging Evidence.
STAT5 activation enhances adoptive therapy combined with peptide vaccination by preventing PD-1 inhibition.
Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response.
The predictive role of PD-L1 expression and CD8 + TIL levels in determining the neoadjuvant chemotherapy response in advanced ovarian cancer.
A dendritic cell vaccine for both vaccination and neoantigen-reactive T cell preparation for cancer immunotherapy in mice.

J Surg Oncol. 2024 Nov 28.

Comment on "Dense Tumor-Infiltrating Lymphocytes (TILs) in Liver Metastasis From Colorectal Cancer Are Related to Improved Overall Survival".

Fuji Lai, Sheng Li, Zhonglei Shen.

DOI: https://doi.org/10.1002/jso.27968
Cureus. 2024 Nov;16(11): e74194

The Role of Lymphocytic Infiltrates in the Tumor Microenvironment as a Predictive Factor for the Response to Immunotherapy in Solid Tumors: A Single-Center Experience From Romania.

Raluca Ioana Mihaila, Adelina Silvana Gheorghe, Daniela Luminita Zob, Dana Stanculeanu.

  The correlation between tumor-infiltrating lymphocytes (TILs) and immunotherapy responses is an evolving field with significant clinical implications. Immunotherapy has revolutionized antineoplastic therapies, offering promising results for patients diagnosed with solid tumors. Integrating biomarkers, refining imaging techniques, and developing non-invasive methods may enhance personalized medicine, optimizing treatment strategies while minimizing adverse effects. In our study, we conducted a retrospective analysis to assess the practicality of utilizing the predictive value of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) correlating the response to immunotherapy in patients with solid tumors, comprehensively navigating through currently available data. Continued research efforts and collaboration between scientists and clinicians are essential to unlock the full potential of these biomarkers and advance the field of immunotherapy in solid tumors.

Keywords:  immunotherapy; oncology; personalized treatment; predictive biomarkers; research; solid tumors; tils; tumor microenvironment; tumor response; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.7759/cureus.74194
Surg Oncol. 2024 Nov 08. pii: S0960-7404(24)00128-2. [Epub ahead of print]57 102160

T-cell immunotherapy for melanoma.

Cristian Mantilla Rosa, Aparna Vancheswaran, Charlotte E Ariyan.

  This review explores T-cell immunotherapy for melanoma, highlighting immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, anti-LAG-3), tumor-infiltrating lymphocytes (TILs), and emerging therapies that engineer T cells with specific receptors or T-cell receptors, such as CAR-T and TCR cells, and RNA vaccines. We discuss the history of T-cell immunotherapy, mechanisms of action, and future directions for improving patient outcomes.

Keywords:  Adoptive T-cell immunotherapy; Checkpoint inhibitors; Melanoma

DOI:  https://doi.org/10.1016/j.suronc.2024.102160
Trends Pharmacol Sci. 2024 Nov 26. pii: S0165-6147(24)00226-8. [Epub ahead of print]

Advances in cell therapy: progress and challenges in hematological and solid tumors.

Claudia D'Avanzo, Franziska Blaeschke, Memnon Lysandrou, Florian Ingelfinger, Robert Zeiser.

  Cell-based therapies harness the endogenous ability of the immune system to fight cancer and have shown promising results in the treatment of hematological malignancies. However, their clinical application beyond B cell malignancies is hampered by numerous hurdles, ranging from relapsed disease to a hostile tumor microenvironment (TME). Recent advances in cell engineering and TME modulation may expand the applicability of these therapies to a wider range of cancers, creating new treatment possibilities. Breakthroughs in advanced gene editing and sophisticated cell engineering, have also provided promising solutions to longstanding challenges. In this review, we examine the challenges and future directions of the most prominent cell-based therapies, including chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes (TILs), and natural killer (NK) cells, and emerging modalities. We provide a comprehensive analysis of emerging cell types and combination strategies translated into clinical trials, offering insights into the next generation of cell-based cancer treatments.

Keywords:  CAR-T cells; antitumor immune response; cell therapy; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.tips.2024.10.016
Cancers (Basel). 2024 Nov 08. pii: 3765. [Epub ahead of print]16(22):

Tumor-Infiltrating B Cells and Tissue-Resident Memory T Cells as Prognostic Indicators in Brain Metastases Derived from Gastrointestinal Cancers.

Masasuke Ohno, Shunichiro Kuramitsu, Kimihiro Yamashita, Toru Nagasaka, Shoichi Haimoto, Mitsugu Fujita.

   BACKGROUND/OBJECTIVES: Tumor-infiltrating B cells (TIBs) and tissue-resident memory T cells (TRMs) play significant roles in antitumor immunity. However, their prognostic relevance in brain metastases (BMs) derived from gastrointestinal (GI) cancers remains unclear. This study aimed to investigate the prognostic significance of TIBs and TRMs in GI cancer-derived BMs (GIBMs).
METHODS: Retrospective histopathological analyses were performed on surgically resected GIBM tissues from 13 patients. The densities of tumor-infiltrating lymphocytes (TIL) subsets (TIBs, CD4+ T cells, CD8+CD103+ TRMs, and CD8+CD103- non-TRMs) were quantified and correlated with clinical parameters and overall survival (OS) including the Graded Prognostic Assessment (GPA).
RESULTS: TIBs and CD4+ T cells were predominantly accumulated in the tumor stroma, particularly around blood vessels, where they formed lymphocyte clusters without characteristics of tertiary lymphoid structures (TLSs). In contrast, TRMs more deeply infiltrated into the tumor epithelium than their counterpart non-TRMs. Positive correlations were found between TIB density and both the prognostic prediction of GPA and overall survival (OS) after BM diagnosis or surgery. Furthermore, increased densities of TIBs and TRMs were associated with enhanced survival after BM diagnosis.
CONCLUSIONS: TIB and TRM densities in BM tissues could serve as reliable prognostic indicators for survival in patients with GIBMs. This study provides crucial insights for the development of novel immunotherapeutic strategies against this lethal disease.

Keywords:  brain metastases; gastrointestinal cancers; prognostic indicators; tertiary lymphoid structures; tissue-resident memory T cells; tumor immune microenvironment; tumor-infiltrating B cells

DOI:  https://doi.org/10.3390/cancers16223765
Front Biosci (Landmark Ed). 2024 Nov 19. 29(11): 385

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Enduring Legacy, Emerging Evidence.

Wei Peng, Yayu Chen, Rong-Quan He, Gang Chen, Daniel Xin Zhang.

DOI: https://doi.org/10.31083/j.fbl2911385
Mol Cancer Ther. 2024 Nov 25.

STAT5 activation enhances adoptive therapy combined with peptide vaccination by preventing PD-1 inhibition.

Aaron E Fan, Hussein Sultan, Takumi Kumai, Valentyna I Fesenkova, Juan Wu, John D Klement, Joshua D Bernstock, Gregory K Friedman, Esteban Celis.

Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1-mediated inhibition in antitumor T cells.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0505
Cell Rep Med. 2024 Nov 19. pii: S2666-3791(24)00602-5. [Epub ahead of print] 101831

Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response.

Jean-Philippe Guégan, Florent Peyraud, Bérengère Dadone-Montaudie, Diego Teyssonneau, Lola-Jade Palmieri, Emma Clot, Sophie Cousin, Guilhem Roubaud, Mathilde Cabart, Laura Leroy, Coriolan Lebreton, Christophe Rey, Oren Lara, Ophélie Odin, Maxime Brunet, Lucile Vanhersecke, Ezogelin Oflazoglu Gruyters, Ikbel Achour, Leila Belcaid, Sylvestre Le Moulec, Thomas Grellety, Alban Bessede, Antoine Italiano.

  Immune checkpoint inhibitors (ICIs) have advanced the treatment of non-small cell lung cancer (NSCLC). This study evaluates the predictive value of CD8+ T cell exhaustion in patients with lung adenocarcinoma treated with ICIs. By analyzing tumor samples from 166 patients through multiplex immunofluorescence, we quantify tumor-infiltrating lymphocytes (TILs) expressing exhaustion markers programmed cell death-1 (PD1), lymphocyte activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell immunoglobulin and mucin domain 3 (TIM3). Their co-expression is associated with ICI resistance, irrespective of programmed cell death ligand-1 (PD-L1) status. We also identify a 25-gene signature indicative of CD8+ T cell exhaustion with high predictive accuracy for ICI response. Validated using several datasets from various clinical trials, this signature accurately predicts ICI responsiveness. Our findings highlight T cell exhaustion's significance in lung adenocarcinoma responses to ICIs and suggest the 25-gene signature as a potential universal biomarker to reinforce precision medicine. This was registered under Clinical Trial registration number NCT02534649.

Keywords:  LAG3; PD1; TIGIT; TIM3; biomarkers; exhaustion; immune checkpoint inhibitors; lung adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2024.101831
J Ovarian Res. 2024 Nov 23. 17(1): 234

The predictive role of PD-L1 expression and CD8 + TIL levels in determining the neoadjuvant chemotherapy response in advanced ovarian cancer.

T Aliyeva, B Y Aktas, F Gundogdu, E Chalabiyev, Z Arik, A Usubutun.

   OBJECTIVE: To analyze how the PD-L1 expression and CD8 + tumor infiltrating lymphocyte (TIL) levels in biopsy samples before neoadjuvant chemotherapy (NACT) can predict chemotherapy response score and survival for advanced high-grade serous ovarian cancer (HGSC).
METHODS: We retrospectively analyzed 45 patients with advanced epithelial ovarian cancer between 2010 and 2018, who had received at least three cycles of NACT. PD-L1 expression and CD8 + TIL levels were evaluated by immunohistochemical staining in the pre-NAC tumor samples from which the patients had been diagnosed. The post-NACT tissue samples taken during interval debulking surgery (IDS) were used to evaluate the chemotherapy response score (CRS).
RESULTS: Among all the patients, CRS 1 (no response) was found in 8 patients, CRS 2 (partial response) in 28 patients, and CRS 3 (complete response) in 9 patients. A total of 20 (44.4%) patients had high intratumoral CD8 + TILs (iCD8 + TILs) levels, and 35 (77.8%) patients had high expression stromal CD8 + TILs (sCD8 + TILs). No statistically significant relationship was found between high and low expression of i/s CD8 + TILs levels with PFS and CRS. The study found that 33 (73.3%) patients had high levels of stromal PD-L1 (sPD-L1) expression and 28 (62.2%) patients had high levels of intratumoral PD-L1 (iPD-L1) expression. In the iPD-L1 group, patients with low expression had a PFS of 28 months, whereas those with high expression had a PFS of 17 months (p = 0.028). Among the patients with high iPD-L1 expression, 23 (82.1%) patients showed CRS2, 4 (14.3%) showed CRS3, and only 1 (3.6%) showed CRS1 (p < 0.001). However, high or low expression sPD-L1 did not significantly affect PFS and CRS (p = 0.928 and p = 0.305; respectively).
CONCLUSIONS: We found that iPD-L1 expression levels in diagnostic biopsy in ovarian cancer can predict the chemotherapy response score in interval debulking surgery.

Keywords:  CRS; Neoadjuvant chemotherapy; Ovarian cancer; PD-L1; TILs

DOI:  https://doi.org/10.1186/s13048-024-01533-x
Nat Commun. 2024 Nov 29. 15(1): 10419

A dendritic cell vaccine for both vaccination and neoantigen-reactive T cell preparation for cancer immunotherapy in mice.

Qing Li, Hao Zeng, Ting Liu, Peipei Wang, Rui Zhang, Binyan Zhao, Tang Feng, Yuling Yang, Jiumei Wu, Yue Zheng, Bailing Zhou, Yang Shu, Heng Xu, Li Yang, Zhenyu Ding.

Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficult isolation of neoantigen-specific T cells limits the clinical application of ACT. Here, we propose a method to prepare neoantigen-reactive T cells (NRT) for ACT following immunization with a tumor lysate-loaded dendritic cell (DC) vaccine. We show that the DC vaccine not only induces a neoantigen-reactive immune response in lung cancer-bearing mice in vivo, but also facilitate NRT cell preparation in vitro. Adoptive transfer of the NRTs as combinatorial therapy into DC vaccine-immunized, LL/2 tumor-bearing mice allows infiltration of the infused NRTs, as well as the enrichment of neoantigen reactive, non-ACT/NRT T cells into the tumor microenvironment with the function of these neoantigen-reactive T-cell receptors validated in vitro. In summary, we propose a method for preparing NRTs that increases ACT efficacy and paves the way to the design of personalized immunotherapies.

DOI: https://doi.org/10.1038/s41467-024-54650-y