FOLR2+ macrophages as immuno-modulators during the carcinogenesis onset: a molecular and spatio-temporal approach

• Grant number: 24/04450-5
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: November 01, 2024
• End date: October 31, 2029
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Rodrigo Nalio Ramos
• Grantee: Rodrigo Nalio Ramos
• Host Institution: Unidade São Paulo. Instituto D'Or de Pesquisa e Ensino (IDOR). Rede D'Or São Luiz (RDSL). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Camila Motta Venchiarutti Moniz ; Eduardo Magalhães Rego ; Felipe Mateus dos Santos Ornellas ; Fernando Augusto Soares ; Helder Takashi Imoto Nakaya ; Humberto Carvalho Carneiro ; Isabela Werneck da Cunha ; Mariana Petaccia de Macêdo ; Otávio Cabral Marques ; Tiago da Silva Medina ; Vanderson Geraldo Rocha
• Associated scholarship(s): 25/13029-4 - Investigation of the Epigenetic and Transcriptional landscape of FOLR2+ Macrophages during Colorectal Cancer onset, BP.DR; 25/02807-6 - The influence of the folate on the interaction between macrophages and the neural stroma in colorectal cancer, BP.DR; 24/14683-7 - Analysis of the contribution of FOLR2+ Macrophages in the formation of Tertiary Lymphoid Structures in Colorectal Cancer, BP.DD

Abstract

Colorectal cancer (CRC) has increased in last decades and represents nowadays the second leading cancer in young adults in Brazil and worldwide. Because it has become a public health issue, fundamental scientific questions focusing on the understanding of the early carcinogenic process may considerably contribute to the precocious CRC diagnosis and treatment. Important sensitive elements pre-existent during the tumor establishment and growth are the resident immune cells. Among them, we have recently described the tissue-resident macrophage expressing the folate receptor-2 (FOLR2+ TRM), present in the non-tumoral tissues and in the stroma/invasive margin of distinct tumor types. In breast cancer, FOLR2+ TRM form stable interactions with CD8+ T cells and positively correlates with various anti-tumoral immune players and tertiary lymphoid structures (TLS). In addition, FOLR2+ TRM isolated from established tumors up-regulated key genes related to immunity stimulation, chemo-attractive factors, cytokines and co-stimulatory surface molecules, when compared to those obtained from healthy mammary glands. Hence, FOLR2+ TRM has emerged as a potential immune-thermometer biomarker during cancer onset. Thus, we propose here to delineate the spatio-temporal, the molecular and the functional profiles of FOLR2+ TRM since the early pre-malignant lesions until established metastatic CRC. We aim to develop three main complementary axes: 1) Uncover the spatial transcriptomic profiling of FOLR2+ TRM from adenomas polypus to CRC tumors implying the Digital Spatial Profiling (DSP GeoMX, Nanostring); 2) Reveal the FOLR2+ TRM contribution to tertiary lymphoid structures (TLS) formation and/or support in CRC patients; and 3) Modeling the tumoral influence on the molecular FOLR2+ macrophages feature by implying a 3D spheroid approach. We believe that this detailed profiling of macrophages will strongly contribute for clinical prognostic and/or diagnostic decisions and will allow, at long-term, the development of comprehensive clinical interventions for immune cell reprogramming for tumor control. (AU)