Resistance to BRAF inhibitors and its impacts on the immune microenvironment in melanoma patients

VEIGAS, FLORENCIA; MAHMOUD, YAMIL; TORRES, NICOLAS; CUTINE, ANABELA M.; MORALES, ROSA; GATTO, SABRINA; PEREZ SAEZ, JUAN MANUEL; MARIÑO, KARINA VALERIA; RABINOVICH, GABRIEL A.; GIROTTI, MARÍA ROMINA

Sao Paulo

Conferencia; Second AACR International Conference Translational Cancer Medicine Cancer Discoveries for Clinical Application; 2018

American Association for Cancer Research

Melanoma is a deadly form of skin cancer and ~20% of melanoma cases are diagnosed in the metastatic stage of the disease. BRAF is mutated in ~50% of melanoma but although targeted therapies based on BRAF/MEK inhibitor combinations increase survival, mostpatients develop resistance after ~10 months. Preclinical and translational studies have shown that targeting the RAS/BRAF/MEK/ERK pathway has effects on the expression of immunomodulatory pathways. Immunotherapy, based on antibodies targetingimmunomodulatory molecules such as CTLA-4, PD-1 and PD-L1, is a true paradigm shift in the treatment of melanoma. In terms of lives saved and person-years restored, immunotherapy promises to be more significant than any other form of treatment for patientswhose tumors have already metastasized. However, there is still a ~70% of melanoma patients that do not respond to immunotherapies and most patients who develop resistance to targeted therapies derive little benefit from anti-CTLA-4 and anti PD-1 basedimmunotherapies. Changes in protein glycosylation during tumor progression confer functional advantages to cancer cells and promotion of metastasis. Glycan and galectin expression patterns are also regulated during the course of an immune response. Galectinsaffect effector T-cells, inducing apoptosis by galectin binding to glycosylated CD45, CD43 or TIM-3. Moreover, galectin-1 (Gal1) activates regulatory circuits in dendritic and T-cells contributing to immune escape and tumor progression.With the ultimate goal of developing novel therapeutic strategies, we study how glycan/galectin interactions contribute to immune escape in metastatic melanoma resistant to targeted therapies and immunotherapies.