Regulation of CD8+ T cell immune responses by STAT3 signaling in type 1 dendritic cells

• Grant number: 25/04936-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 02, 2025
• End date: September 01, 2026
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Silvia Beatriz Boscardin
• Grantee: Guilherme Antonio de Souza Silva
• Supervisor: Henrique Borges da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Mayo Clinic In Arizona, United States
• Associated to the scholarship: 22/00204-4 - Influence of the STAT5 signaling pathway in conventional dendritic cells on the instruction of helper T cell response, BP.DD

Abstract

Conventional type 1 dendritic cells (cDC1s) play a pivotal role in orchestrating anti-tumor immunity by cross-presenting antigens and priming CD8¿ T cell responses. Our previous work, utilizing DEC205-mediated antigen targeting, demonstrated robust induction of antigen-specific CD8¿ T cells and effective tumor control in preclinical models. However, the contribution of STAT3 signaling within cDC1s to this process remains poorly defined. Preliminary data indicate that deletion of STAT3 in dendritic cells impairs pro-inflammatory CD8¿ T cell responses and diminishes tumor control, suggesting a critical role for STAT3 in cDC1 function. This project aims to elucidate the mechanistic role of STAT3 signaling in cDC1-mediated CD8¿ T cell activation following DEC205 receptor targeting. Specifically, we will (i) characterize the kinetics, anatomical distribution, and phenotypic profile of tumor antigen-specific CD8¿ T cell subpopulations in STAT3 conditional knockout (cKO) versus control mice immunized with DEC205-antigen conjugates (HPV16 E7 and OVA); (ii) assess the functional competence of STAT3-deficient cDC1s through in vitro antigen-pulsing and adoptive transfer experiments. Moreover, the generation and use of XCR1-CRE-STAT3Flox/Flox mice will allow us to restrict STAT3 deletion specifically to the cDC1 subset, thereby refining our understanding of its immunological impact. By integrating flow cytometry, confocal imaging, and transcriptomic analyses in well-established tumor models, our study will provide novel insights into the immunobiology of cDC1s and the role of STAT3 in anti-tumor CD8¿ T cell responses. The proposed BEPE scholarship at the Mayo Clinic will facilitate access to advanced methodologies, overcoming current resource limitations in Brazil and fostering international collaboration to advance cancer immunotherapy. (AU)