Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma

Abstract

Summary 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.

Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

“…Comparing pre-and on-treatment measurements, we noted a significant increase in LAIR1, TREX1, and LILRB2 expression among tumors with partial and complete response, but no change among patients with progressive disease (Figure 7D). These increases are consistent with remodeling of the composition of the TIME in responders, as was recently reported in another immunotherapy study with on-treatment profiling 54 . Moreover, they imply these genes may drive responses to ICB in cancer patients.…”

Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma

“…Very recently, Anagnostou et al described the mutations and their expression in various types of metastatic melanomas studied in the CheckMate-038 ( https://clinicaltrials.gov/ct2/show/results/NCT01621490 ) clinical trial [ 20 ]. One uveal melanoma metastasis (case MUM-20035) carried a copy number stable heterozygous CYSLTR2 mutation which was also hemizygously expressed at the RNA level (Fig.…”

“…Recently, the CYSLTR2 mutation was also detected in metastasising uveal melanomas [ 20 , 27 – 29 ]. None of those cases displayed chromosome 13q copy number alterations involving CYSLTR2 , but for one metastatic lesion we were able to analyse the CYSLTR2 allelic balance in detail (Fig.…”

“…DNA and RNA levels of the CYSLTR2 mutation in metastatic uveal melanoma CheckMate-03820,035 were available from the recent study performed by Anagnostou et al [ 20 ].…”

“…The data sets analysed during the current study are available via the Broad GDAC Firehose ( https://gdac.broadinstitute.org ), NCI Genomic Data Commons data portal (GDC; https://portal.gdc.cancer.gov ), Gene Expression Omnibus repository ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139829 ) and (supplementary) files of the original publications [ 13 , 14 , 20 ].…”