Comprehensive characterization of T cells in Pancreatic Ductal Adenocarcinomas

• Grant number: 19/25129-2
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): October 01, 2020
• Effective date (End): September 30, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Tiago da Silva Medina
• Grantee: Gabriela Sarti Kinker
• Host 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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

KINKER, GABRIELA SARTI; VITIELLO, GLAUCO AKELINGHTON FREIRE; FERREIRA, WALLAX AUGUSTO SILVA; CHAVES, ALEXANDRE SILVA; CORDEIRO DE LIMA, VLADMIR CLAUDIO; MEDINA, TIAGO DA SILVA. B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, JUN 7 2021. (18/14034-8, 19/25129-2, 14/50943-1)