TY - JOUR

T1 - BRAF inhibition improves tumor recognition by the immune system

T2 - Potential implications for combinatorial therapies against melanoma involving adoptive T-cell transfer

AU - Donia, Marco

AU - Fagone, Paolo

AU - Nicoletti, Ferdinando

AU - Andersen, Rikke Sick

AU - Høgdall, Estrid

AU - Straten, Per Thor

AU - Andersen, Mads Hald

AU - Svane, Inge Marie

PY - 2012

Y1 - 2012

N2 - In spite of the fact that they occur at high rates, the clinical responses of BRAF(V600) mutant metastatic melanoma to BRAF inhibitors are usually short-lasting, with most cases progressing within less than 8 mo. Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer, which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma. Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAF(V600) mutant melanoma cell lines in vitro. Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8(+) T cells. Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins. In conclusion, our preclinical data suggest that an appropriately timed sequential treatment of BRAF(V600) mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells.

AB - In spite of the fact that they occur at high rates, the clinical responses of BRAF(V600) mutant metastatic melanoma to BRAF inhibitors are usually short-lasting, with most cases progressing within less than 8 mo. Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer, which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma. Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAF(V600) mutant melanoma cell lines in vitro. Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8(+) T cells. Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins. In conclusion, our preclinical data suggest that an appropriately timed sequential treatment of BRAF(V600) mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells.

U2 - 10.4161/onci.21940

DO - 10.4161/onci.21940

M3 - Journal article

VL - 1

SP - 1476

EP - 1483

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 9

ER -