The immune landscape of renal cell carcinoma and its association with intratumoral clonality.

Abstract

605 Background: Clear cell renal cell carcinoma (ccRCC) is among the most highly infiltrated tumors despite a relatively low mutation burden. Despite success in treating subsets of these patients with immunotherapy, the high immune-infiltration of ccRCC remains a conundrum that has not been sufficiently addressed. Methods: We utilized an original RNAseq-based aggregate immune score (Senbabaoglu Y, bioRxiv, 2015) to compare immune infiltration levels across 20 tumor types profiled in The Cancer Genome Atlas (TCGA) and validated our results with an independent cohort of ccRCC patients (Sato Y, Nat Genet, 2013). We also evaluated the immunogenic effect of intratumoral heterogeneity (ITH) through an analysis of clonal architecture in ccRCC tumors from both of the aforementioned data sets using the SciClone (Miller C, PLoS Comput Biol, 2014) algorithm. Results: We identified ccRCC as an immunogenic outlier that is unique from other highly infiltrated tumors in its exceptional overexpression of antigen presentation machinery compared to normal tissue. In a focused decomposition of immune cell levels within the 415 ccRCC tumors from TCGA, three unique clusters of tumors emerged primarily separated by varying degrees of T cell infiltration; termed (1) T-cell-enriched, (2) heterogeneous, and (3) non-infiltrated groups. These clusters were validated in an independent ccRCC cohort of 101 patients. A comparison of the degree of clonality with immune infiltration levels revealed that tumors with less ITH (i.e. fewer subclones) had significantly higher immune infiltration in both the TCGA and the validation cohort . Conclusions: Our findings provide novel insight into the immune landscape of ccRCC tumors and explore a potential mechanism for the immunogenicity of these tumors. Such information can potentially be used to aid in predicting therapeutic response to immunomodulatory agents.