CENTRO DE INVESTIGACION Y DESARROLLO EN INMUNOLOGIA Y ENFERMEDADES INFECCIOSAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Characterization of the immune microenvironment in melanoma patients resistant to targeted and immunotherapies by a multidisciplinary approach
MAHMOUD, YAMIL; PEREZ SAEZ, JUAN MANUEL; GIROTTI, MARÍA ROMINA; FLORES, ANA; ELMER A FERNÁNDEZ; VEIGAS, FLORENCIA; GATTO, SABRINA; RABINOVICH, GABRIEL
Congreso; IMMUNOLOGY 2019; 2019
The American Association of Immunologists, Inc.
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.