cDC1 and Tissue-Resident Exhausted CD8 T Cells Drives Disease Control and Checkpoint Blockade Immunotherapy Response in Melanoma

Cristina Aguilar Flores – UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social; Julian Gajón – Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Mexico City, Mexico; Angel Juarez Flores – Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez, Mexico City, Mexico; Ezequiel M. Fuentes-Pananá – Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez, Mexico City, Mexico; Laura C. Bonifaz – Coordinación de investigación en salud, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Abstract Text: Melanoma is the deadliest form of skin cancer, with a rising incidence in Latin American countries. While immunotherapy has significantly improved melanoma treatment and patient survival, a subset of patients remains unresponsive, emphasizing the need to identify factors critical for successful treatment and to understand disease progression. In this study, we evaluated the presence of conventional dendritic cells type 1 (cDC1) and tissue-resident memory (TRM) CD8 T lymphocytes two key cell types in antitumoral responses in the stroma of melanoma patients using multiplex immunofluorescence and artificial intelligence-based image analysis. Remarkably, we identified two TRM CD8 T-cell populations: one expressing the progenitor marker TCF1 (TCF1+) and another lacking it (TCF1-). TCF1+ TRM cells exhibited heightened expression of IFN-γ and Ki67, while TCF1- TRM cells showed increased expression of cytotoxic molecules and were near apoptotic tumor cells. Spatial analysis revealed a correlation between cDC1s and TRMs, with TCF1+ TRM/cDC1 pairs enriched in the stroma and TCF1- TRM/cDC1 pairs predominantly located in tumor areas. Notably, these immune populations were organized into structured immune niches near the tumor area in disease-free patients, compared to metastatic patients who don’t show these niches. Importantly, in an independent cohort, we observed that both TRM CD8 T-cell populations and cDC1 were highly abundant in patients responding to CBI, even before treatment, suggesting their potential use as predictive biomarkers for treatment selection.