Bioinformatic Immunogenomic Profiling to Reveal Biomarkers of Response to Targeted Therapies and Checkpoints Blockade in Melanoma Patients

YAMIL DAMIÁN MAHMOUD; FLORENCIA VEIGAS; FEDERICO PRADA; KARINA MARIÑO; GABRIEL RABINOVICH; MARÍA ROMINA GIROTTI

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

SAIC, SAI

Abstract: Melanoma is the deadliest form of skin cancer. There has been a paradigm shift in the treatment of melanoma based on the development of targeted therapies and immunotherapies showing unprecedented survival benefits. However, responses are not universal and patients who initially respond develop acquired resistance. Critically, treatment is associated with inflammatory toxicity and high cost. Therefore, determining which patients would derive clinical benefit from immunotherapy is a compelling clinical question. The aim of this study was to determine predictive molecular biomarkers of response to immunotherapy and to quantify the cellular composition of the immune response in order to investigate its relationship with response to treatment. We analyzed the gene expression profiles of melanoma tumor samples from databases with clinical annotation such as The Cancer Genome Atlas (TCGA, n=470), The Cancer Immunome Atlas (TCIA) and public datasets from Gene Expression Omnibus (GEO). For this meta-analysis we implemented an established computational approach (CIBERSORT) based on a deconvolution method to infer the proportion of 22 immune cell types from gene expression profiles. Bioinformatics and statistical analysis were performed with the R programming language and public web tools. Our preliminary findings show a differential molecular signature involved in shaping the immune infiltrate in melanoma tumors sensitive and resistant to targeted therapies (BRAF and/or MEK inhibitors), and also in melanoma tumors responding and non-responding to anti PD-1 blockade. These molecules could be potential biomarkers of response as well as new actionable targets for the development of combination therapies. We also observed differences in the cellular composition of the immune infiltrate in melanoma tumors that are likely to be important determinants of both prognosis and response to treatment.