bims-tuinly 2024-10-20 papers

Adv Sci (Weinh). 2024 Oct 18. e2409356

TIL Therapy in Lung Cancer: Current Progress and Perspectives.

Lung cancer remains the most prevalent malignant tumor worldwide and is the leading cause of cancer-related mortality. Although immune checkpoint blockade has revolutionized the treatment of advanced lung cancer, many patients still do not respond well, often due to the lack of functional T cell infiltration. Adoptive cell therapy (ACT) using expanded immune cells has emerged as an important therapeutic modality. Tumor-infiltrating lymphocytes (TIL) therapy is one form of ACT involving the administration of expanded and activated autologous T cells derived from surgically resected cancer tissues and reinfusion into patients and holds great therapeutic potential for lung cancer. In this review, TIL therapy is introduced and its suitability for lung cancer is discussed. Then its historical and clinical developments are summarized, and the methods developed up-to-date to identify tumor-recognizing TILs and optimize TIL composition. Some perspectives toward future TIL therapy for lung cancer are also provided.

Keywords: Adoptive cell transfer (ACT); Lung cancer; Non‐small cell lung cancer (NSCLC); Tumor‐infiltrating lymphocytes (TILs); Tumor‐reactive T cells

DOI: https://doi.org/10.1002/advs.202409356

Biomed Pharmacother. 2024 Oct 16. pii: S0753-3322(24)01430-6. [Epub ahead of print]180 117544

The prognostic value of tumor-infiltrating lymphocytes in head and neck squamous cell carcinoma: A systematic review and meta-analysis.

Meri Torri, Adam Sandell, Ahmed Al-Samadi.

Head and neck squamous cell carcinoma (HNSCC) is experiencing a rising incidence and mortality worldwide, emphasizing the need for reliable prognostic markers. Tumor-infiltrating lymphocytes (TILs) have emerged as a promising biomarker for predicting HNSCC prognosis, yet no systematic reviews have exclusively focused on hematoxylin and eosin (H&E)-stained formalin-fixed paraffin-embedded (FFPE) samples, which are routinely used in clinical practice. This systematic review and meta-analysis followed the PRISMA guidelines to examine the prognostic value of TILs in HNSCC using H&E-stained FFPE samples. Data were pooled from 43 studies, including 26 studies in a meta-analysis, analyzing 5037 HNSCC samples. We found that a high TIL count associated with a significantly improved overall survival (OS) (HR 0.47, 95 % CI 0.41-0.55, p < 0.0001), disease-free survival (DFS) (HR 0.55, 95 % CI 0.41-0.55, p < 0.0001), and disease-specific survival (DSS) (HR 0.58, 95 % CI 0.46-0.73, p < 0.0001). The heterogeneity was moderate for the pooled analysis (OS: I² = 40 %; DFS: I² = 39 %; DSS: I² = 51 %), but low for the subgroup analysis based on tumor site in oral, oropharyngeal, laryngeal, and nasopharyngeal cancer (OS and DFS: I² = 0-14 %). This review is the first to systematically evaluate TILs in HNSCC using H&E-stained samples, confirming their prognostic value. A high TIL count is associated with improved survival outcomes, suggesting their potential as prognostic biomarkers in clinical settings.

Keywords: Biomarker; Cancer; H&E staining; Head and neck cancer; Meta-analysis; Tumor-infiltrating lymphocytes

DOI: https://doi.org/10.1016/j.biopha.2024.117544

Virchows Arch. 2024 Oct 12.

Relationships between tumor CD147 expression, tumor-infiltrating lymphocytes, and oncostatin M in hepatocellular carcinoma.

Yasuyuki Shigematsu, Hiroaki Kanda, Yu Takahashi, Kengo Takeuchi, Kentaro Inamura.

In hepatocellular carcinoma (HCC), CD147 expression contributes to tumor malignancy; however, its relationship with the tumor-immune microenvironment (TIME) remains unclear. This study aimed to elucidate the clinicopathological characteristics associated with CD147 expression in HCC and investigate its association with the TIME, specifically its association with tumor-infiltrating lymphocytes (TILs) and oncostatin M (OSM). Using 397 HCC specimens from patients undergoing curative-intent resection, we assessed CD147 expression in tumor cells and quantified OSM-positive cells and various TILs (CD8+, CD4+, FOXP3+, and CD20+ cells) in the TIME. Using tissue microarrays, these assessments were performed through immunohistochemical analysis. We investigated the associations between CD147 expression status, the density of OSM-positive cells, and the densities of various TILs. High CD147 expression, found in 332 specimens (83.6%), was associated with advanced clinical stage (P = 0.029), fibrosis (P = 0.036), and higher densities of FOXP3+ cells (P = 0.0039), CD4+ cells (P = 0.0012), and OSM-positive cells (P = 0.0017). In CD147-high tumors, OSM-positive cell density was associated with all assessed TIL subsets (CD8+, CD4+, FOXP3+, and CD20+ cells; all Ps < 0.001), whereas in CD147-low tumors, OSM-positive cell density was associated only with FOXP3+ cells (P = 0.0004). In HCC, CD147 expression is associated with an immunosuppressive TIME, characterized by increased FOXP3+ regulatory T cells and a correlation with OSM-positive cells. These results elucidate the potential mechanisms through which CD147 facilitates tumor-immune evasion, suggesting the CD147 - OSM axis as a promising target for therapeutic intervention in HCC.

Keywords: CD147; Hepatic fibrosis; Immunity; Immunohistochemistry; Liver cancer; Oncostatin M; Regulatory T cells; Tumor-immune microenvironment

DOI: https://doi.org/10.1007/s00428-024-03939-w

Cancer Immunol Res. 2024 Oct 15.

Preclinical development of T cells engineered to express a T cell antigen coupler (TAC) targeting Claudin 18.2-positive solid tumors.

Stacey X Xu, Ling Wang, Philbert Ip, Ritu R Randhawa, Tania Benatar, Suzanna L Prosser, Prabha Lal, Alima Naim Khan, Thanyashanthi Nitya-Nootan, Gargi Thakor, Heather MacGregor, Danielle Hayes, Andrea Vucicevic, Princy Mathew, Sadhak Sengupta, Christopher W Helsen, Andreas G Bader.

The T cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T cell receptor complex in the absence of tonic signaling. Previous data demonstrates that TAC affords T cells with the ability to induce durable and safe anti-tumor responses in preclinical models of hematological and solid tumors. Here, we describe the preclinical pharmacology and safety of an autologous Claudin 18.2 (CLDN18.2)-directed TAC T cell therapy, TAC01-CLDN18.2, in preparation for a Phase I/II clinical study in subjects with CLDN18.2-positive solid tumors. Following a screen of putative TAC constructs, the specificity, activity, and cytotoxicity of TAC T cells expressing the final CLDN18.2-TAC receptor were evaluated in vitro and in vivo using gastric, gastroesophageal, and pancreatic tumor models as well as human cells derived from normal tissues. CLDN18.2-specific activity and cytotoxicity of CLDN18.2-TAC T cells were observed in coculture with various 2D tumor cultures naturally expressing CLDN18.2 as well as tumor spheroids. These effects occurred in models with low antigen levels and was positively associated with increasing CLDN18.2 expression. CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting anti-tumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0138