In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade.,Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome.,Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders.,Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome.,High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response.,These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.,Unmet need for integrated molecular models that interpret immunotherapy responseGenomic, transcriptomic, and T and B cell sequence data integration by machine learningT cell dynamism is a hallmark of response to immune checkpoint blockadeThe combined contributions of B, T, and tumor cell features predict clinical outcome,Unmet need for integrated molecular models that interpret immunotherapy response,Genomic, transcriptomic, and T and B cell sequence data integration by machine learning,T cell dynamism is a hallmark of response to immune checkpoint blockade,The combined contributions of B, T, and tumor cell features predict clinical outcome,Anagnostou et al. integrate genomic, expression, and immune cell repertoire analyses to gain insights into the crosstalk between cancer and immune cells during immunotherapy for melanoma.,These findings suggest that the complex phenotype of tumor immune infiltrates combined with genomic features of tumor cells are relevant for determining clinical outcomes.
Melanoma is one of the most aggressive cancers and its incidence is increasing worldwide.,So far there are no curable therapies especially after metastasis.,Due to frequent mutations in members of the mitogen-activated protein kinase (MAPK) signaling pathway, this pathway is constitutively active in melanoma.,It has been shown that the SONIC HEDGEHOG (SHH)-GLI and MAPK signaling pathway regulate cell growth in many tumors including melanoma and interact with each other in the regulation of cell proliferation and survival.,Here we show that the SHH-GLI pathway is active in human melanoma cell lines as they express downstream target of this pathway GLI1.,Expression of GLI1 was significantly higher in human primary melanoma tissues harboring BRAFV600E mutation than those with wild type BRAF.,Pharmacologic inhibition of BRAFV600E in human melanoma cell lines resulted in decreased expression of GLI1 thus demonstrating interaction of SHH-GLI and MAPK pathways.,Inhibition of SHH-GLI pathway by the novel small molecule inhibitor of smoothened NVP-LDE225 was followed by inhibition of cell growth and induction of apoptosis in human melanoma cell lines, interestingly with both BRAFV600E and BRAFWild Type status.,NVP-LDE225 was potent in reducing cell proliferation and inducing tumor growth arrest in vitro and in vivo, respectively and these effects were superior to the natural compound cyclopamine.,Finally, we conclude that inhibition of SHH-GLI signaling pathway in human melanoma by the specific smoothened inhibitor NVP-LDE225 could have potential therapeutic application in human melanoma even in the absence of BRAFV600E mutation and warrants further investigations.