Abstract 974: The molecular and genomic drivers of immunologically cold tumors: Novel discoveries from pan-cancer analysis

Immune-checkpoint blockade (ICB) is able to elicit remarkable immune response but currently the durable response is limited to a minority of cancer patients. Recent evidence suggests that a prerequisite for the efficacy of ICB, for example the PD-1 inhibitor, is T-cells infiltration in the tumor microenvironment (TME). The immunologically ‘quite’ and T-cell depleted (immune ‘desert’) tumors are less likely respond to ICB. However, we still lack a detailed understanding of the genomic and molecular determinants that drive the ‘cold’ immune phenotypes. We here performed a comprehensive pan-cancer analysis to define and characterize the immunologically ‘hot’ (inflamed) and ‘cold’ (quite or T-cell depleted) tumors by high-dimensional, multi-platform data integration of 9,887 tumors from The Cancer Genome Atlas (TCGA). This study provided an unprecedented catalog of the molecular and genomic drivers of immune ‘cold’ tumors by analyzing the immune cell composition, patterns of their spatial organization within the TME, the dysregulated chemokines networks, somatic mutations, DNA copy-number alterations, aneuploidy status, differentially expressed immune regulatory genes, and enriched signaling pathways. We showed that the immunologic status is highly heterogeneous within and across TCGA tumor types and subtypes. We integrated the information of T-cell spatial organization with our immune phenotypes and found that the ‘band-like’ spatial organization (T cells clustered at the invasive margin of the tumor and didn’t get into the tumor body) pattern is strongly associated with the ‘cold’ phenotype, particularly in colon and stomach cancers. Our analysis revealed a number of other factors that are associated with the ‘cold’ phenotype by either preventing T-cell infiltration or promoting T-cell dysfunction, and we performed functional validation on several targets of interest. This study provided an in-depth understanding of the genomic and molecular determinants of immunologically ‘cold’ tumors and suggested potential biomarkers that can be targeted for the development of novel combination therapy strategies to convert the ‘cold’ tumors into ‘hot’ ones and improve the odds of cancer immunotherapy success.Citation Format: Guangchun Han, Ruiping Wang, Jianfeng Shen, Pankaj Singh, Shaojun Zhang, Arvind Rao, Jianjun Gao, Alexander Lazar, Andrew Futreal, Guang Peng, Kunal Rai, Linghua Wang. The molecular and genomic drivers of immunologically cold tumors: Novel discoveries from pan-cancer analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 974.