Abstract
Current immunotherapies are effective only in a subset of patients, likely due to several factors including defects in tumor cell antigen presentation, decreased response to immune effectors, and molecular heterogeneity of cancers. Recent molecular classifications enable the categorization of many tumor types. However, deregulation of major histocompatibility complex (MHC) gene expression is poorly characterized in the context of molecular cancer subtypes. To suppress the confounding effect of immune infiltrates on expression patterns of immunoregulators, we identified and removed genes with strong correlation to estimated immune compartment levels in each tumor type. Next, we reanalyzed a total of 13 TCGA cancer types encompassing 5651 tumors and 485 normal adjacent tissues by performing unsupervised clustering of 14 MHC genes. Subsequently, resultant clusters were statistically compared in terms of expression of other immune-related genes. Three MHC expression clusters were discovered by unsupervised clustering. We identified concordantly decreased expression of MHC genes (MHC-low) in 26 out of 55 molecular subtypes. Consequently, our study underlines the urgent need for designing strategies to enhance tumor MHC expression that could improve immune cold tumor rejection by cytotoxic T lymphocytes.
Highlights
Immune cells present in the tumor microenvironment (TME) can either inhibit or enhance tumor growth
Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under phase III and IV clinical trials [5]
We focused on cancer subtypes with a concordant decrease of major histocompatibility complex (MHC) expression when compared to corresponding normal adjacent tissue
Summary
Immune cells present in the tumor microenvironment (TME) can either inhibit or enhance tumor growth. Heterogeneity of the TME is determined by the composition of different cell types in the tumor and their activation state, which is regulated by molecular signals to which these cells are exposed [1]. Tumor cells are able to exploit various mechanisms of immune regulation to suppress activity of immune cells within the TME, avoiding antitumor immunity [3]. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments (e.g., melanoma), while others are under phase III and IV clinical trials [5]. Despite the success of anti-CTLA-4 and anti-PD-1/PD-L1 therapies, current ITs are only effective in a subset of patients, likely due to the molecular heterogeneity of cancer types
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