CIDIE   24052
CENTRO DE INVESTIGACION Y DESARROLLO EN INMUNOLOGIA Y ENFERMEDADES INFECCIOSAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Characterization of the immune microenvironment in melanoma patients resistant to targeted and immunotherapies by a multidisciplinary approach
Autor/es:
MAHMOUD, YAMIL; PEREZ SAEZ, JUAN MANUEL; GIROTTI, MARÍA ROMINA; FLORES, ANA; ELMER A FERNÁNDEZ; VEIGAS, FLORENCIA; GATTO, SABRINA; RABINOVICH, GABRIEL
Lugar:
San Diego
Reunión:
Congreso; IMMUNOLOGY 2019; 2019
Institución organizadora:
The American Association of Immunologists, Inc.
Resumen:
AbstractMost melanoma patients who develop resistance to targeted therapies do not respond to subsequent immunotherapy. Therefore, establishing which patients would derive clinical benefit from immunotherapy is a compelling clinical question. We performed a meta-analysis of published transcriptome datasets from melanoma biopsies before and after development of resistance to BRAFi or BRAFi/MEKi. We observed an increase in M2-macrophages infiltrate by CIBERSORT in relapsed biopsies as well as an increase in T-cell exhaustion markers and immunosuppressive cytokines. Our preliminary findings show changes in the galectin/glycan axis in melanoma resistance to BRAFi/MEKi. Particularly, we observed that the expression of Galectin-1 (Gal-1) is increased in human melanoma resistant cells. We analyzed single-cell and bulk RNA-Seq gene expression profiles from melanoma biopsies before and during treatment with anti-PD-1/anti-CTLA-4 and found that macrophages and CD8 T-cells of non-responders upregulate a specific glycosylation-related signature. Macrophages from non-responding patients show an immunosuppressive expression profile accompanied by the appearance of a novel sub-group during treatment associated with resistance. We hypothesize that there are Gal-1/glycan interactions that promote an M2 immunosuppressive microenvironment in resistant tumors preventing response to immunotherapy. Finally, we developed MIXTURE, a novel algorithm to infer the tumor immune infiltrate that overcomes CIBERSORT limitations. MIXTURE analysis revealed a differential immunosuppressive infiltrate in melanoma biopsies with high intratumoral heterogeneity and in biopsies from non-responding patients to anti PD-1 immunotherapy.