Evaluation of the antitumoral activity of CD39+ T cells in patients with clear cell renal cell carcinoma

• Grant number: 22/00747-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2023
• Effective date (End): October 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Tiago da Silva Medina
• Grantee: Emmanuel Vinicius Oliveira Araujo
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Associated research grant: 18/14034-8 - Characterization of chromatin and transcriptional landscapes of T cells from gastric adenocarcinoma patients as a tool to discover immunotherapy targets, AP.JP

Abstract

With the advent of the immune checkpoint blockade (ICB), immunotherapy has revolutionised the way how cancer patients have been treated over the last years. Groundbreaking advances have been achieved upon cancer patient treatment with anti-PD-1 and anti-CTLA-4. However, globally, only 30-50% of cancer patients respond partially or completely to anti-PD-1 and/or anti-CTLA-4. In clear cell renal cell carcinoma (CCRCC), only a minority of patients derive durable benefits, and mechanisms of resistance remain poorly understood. This particularity is most likely due to interpatient heterogeneity within the tumor and immune cell compartments. The immune response is mostly effective when meticulously compartmentalised and organised within cellular aggregates, as it is within secondary lymphoid organs distributed throughout the human body, such as lymph nodes and spleen. From an evolutionary perspective, such organisation facilitates cell-to-cell interaction and communication that ultimately leads to potent immune responses to exogenous or tumor antigens. Therefore, the comprehensive understanding of the spatial organisation of intratumor immune cells, particularly in ectopic tertiary lymphoid structures (TLSs) formed during tumor progression, has recently gained momentum. Of note, our preliminary data point to the clinical benefit of TLS formation and maturation in pancreatic ductal adenocarcinoma (PDAC) patients. In a pancancer analysis, we have shown that CD39+CXCL13+ T cells are organised within TLSs, undergo clonal expansion and acquire an exhaustion signature that phenotypically resembles tumor-reactive T cells. Across all tumours analysed, renal cell cancer presented the most robust results. To provide substantial evidence that T cells within TLSs are indeed tumor-reactive cells, we will deeply analyse the functional participation of CD39+ T cells in CCRCC patients. Thus, we will analyse (i) the gene expression of intratumor CD39+ T cells sorted from CCRCC patients relative to CD39- T cells, (ii) will phenotypically characterise T and B cells through multiparametric flow cytometry, immunofluorescence, and immunohistochemistry, (iii) will evaluate the proliferative capacity and expression of functional markers in CD39+ T cells vs CD39- T cells, (iv) will perform co-culture assays with tumor cells to evaluate the killing potential of CD39+ T cells vs CD39- T cells, (v) will evaluate whether the presence of mature TLSs is associated with better response to immunotherapy, and (vi) will exploit public datasets of CCRCC patients. Owing to the antitumoral T cell specificity, we believe that reversing the CD39+ T cell exhaustion status, particularly from those organised within TLSs, might be clinically relevant to the treatment of CCRCC patients.