Characterisation of the spatial organisation and functions of tumour-infiltrating immune cells in endometrial cancer patients as a strategy for discovering immunotherapy targets

• Grant number: 24/01953-6
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2024
• End date: April 30, 2027
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandre André Balieiro Anastácio da Costa
• Grantee: Maria Luisa Marques Pierre
• 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

Endometrial cancer has an increasing incidence and disease-associated mortality, being the most common gynecological cancer in developed countries. Furthermore, the endometrial immune system is unique: besides acting as a protective barrier against external pathogens, it is modulated by the menstrual cycle and can adopt an immunosuppressive profile, which aids pregnancy development. However, in the context of endometrial cancer, the highly immunosuppressive tumor microenvironment impacts the local immune response and drives T cells towards a dysfunctional phenotype. The frequency of regulatory T lymphocytes increases, the effector capacity of CD8+ T cells decreases, and the immune cells become ineffective in eliminating tumor cells. Therefore, immunotherapies aim to reinvigorate dysfunctional tumor-reactive lymphocytes as a strategy for tumor control. Immune checkpoint inhibitors have emerged as promising tools to modulate the immune response in the tumor microenvironment, and anti-PD1 currently is the main immune checkpoint inhibitor. It is known that the anti-PD1 has been effective in modulating the immune response, particularly enhancing the cytotoxic function of CD8+ T cells. However, approximately 75% of patients with endometrial cancer do not respond to anti-PD1 treatments, which suggests that intratumoral immune response is heterogeneous among patients. Moreover, the immune response is more efficient when lymphocytes are organized in aggregates, such as tertiary lymphoid structures (TLSs), which facilitate cell-to-cell interaction and communication. Therefore, understanding how these cells are organized within TLSs might be crucial to identify molecular candidates capable of reorganizing lymphocytes within TLSs as a strategy to boost antitumor responses. Pioneering evidence from our group has demonstrated that mature TLSs are key niches of antitumor T and B cells. In this project, to deeply assess the relevance of immune cells organized within TLSs, we will comprehensively characterize immune cells from surgical specimens and/or biopsies from patients with endometrial cancer, evaluating their functionality and organization in the tissue. Thus, we aim to investigate the determinants of the antitumor response that correlate with better clinical development to discover possible targets that enhance the antitumor response and open new perspectives for the treatment of endometrial cancer.