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Comprehensive characterization of T cells in Pancreatic Ductal Adenocarcinomas

Grant number: 19/25129-2
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2020
Effective date (End): September 30, 2022
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Tiago da Silva Medina
Grantee:Gabriela Sarti Kinker
Home Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a median survival of <11 months. Surgical resection is the only potentially curative therapeutic option, and emerging strategies to improve PDA prognosis include the molecular stratification of tumors into biologically homogenous subgroups, and the development of immunotherapies. Over the past years, immune checkpoint inhibitors that boost T cell activity and reinvigorate antitumor immunity have begun to transform clinical oncology. Owing to persistent antigen exposure, tumor-infiltrating lymphocytes usually become dysfunctional/exhausted, and express immune checkpoints such as programmed cell death 1 (PD1). Antibodies that block the PD1-PD1 ligand 1 (PDL1) axis have been approved as first/second-line therapies for a growing list of malignancies, however only a minority of patients derive durable benefits. In PDA, anti-PD1/PDL1 monotherapy has very limited efficacy (~3%), and mechanisms of resistance remain poorly understood. There is thus a clear need for a comprehensive characterization of the immune component of such tumors in order to rationally design therapeutic regimens that maximize clinical benefits. Here, using single cell RNA-seq (scRNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq) and in vitro assays, we will dissect the transcriptional, epigenetic and functional landscape of T cells in PDA, and explore their network of interactions with other leucocytes. With that, we can i) provide the framework for understanding PDA resistance to anti-PD1/PDL1; ii) identify more suitable target molecules for immunotherapy; and iii) pave the way for combinatorial therapies involving novel pharmacological strategies (e.g. epigenetic modulators) for effective T cell reprogramming. (AU)