Tumor genomic alterations in severe-combined immunodeficiency bare-lymphocyte syndrome genes are associated with high mutational burden and disproportional neo-antigen rates

Yu Wang,Justin M Balko,Yaomin Xu,Douglas B Johnson,Luis A Diaz,Steve Lu

doi:10.1186/s40425-019-0584-2

Abstract

The progression of cancer requires mutational adaptation to permit unrestrained proliferation. A fraction of cancer mutations are oncogenic drivers, while others are putative ‘passengers’ that do not contribute to oncogenesis. However, altered peptides arising from passenger mutations may bind MHCs and activate non-self immunologic signals (i.e. neoantigens), thus requiring immunoediting for cancer persistence. Disruption of antigen processing machinery in tumor cells may diminish this requirement. Here, we show that rare mutations in antigen processing machinery are associated with high mutational burden and increased predicted neoantigen load, providing insights into the mechanisms of high mutation burden in some patients.

Highlights

Cancer-expressed neoantigens are a major determinant of immunological activity and response to immunotherapy [1,2,3,4,5,6,7,8,9]
We identified sporadic mutations in bare lymphocyte syndrome (BLS) genes (MHC-I and MHC-II) across cancer types, some of which were recurrent (Additional file 1: Figure S1)
Within each database, tumors harboring BLS mutations were strongly associated with a higher tumor mutational burden (TMB) (p = 1.42e-17 to 8.82e-75 for all comparisons; Fig. 1a) compared to non-BLS-altered, suggesting that putative disruption of MHC-I or MHC-II antigen presentation may eliminate or reduce the requirement for immune-editing of the tumor by permiting the generation of neoantigens without an immune-mediated consequence

Summary

Introduction

Cancer-expressed neoantigens are a major determinant of immunological activity and response to immunotherapy [1,2,3,4,5,6,7,8,9]. BLS is a rare hereditary immunodeficiency syndrome characterized by loss-of-function germline alterations in MHC machinery (i.e. those molecules required for expression of MHC as well as peptide/antigen loading and transport) [18]. Type II BLS results from alterations in CIITA, RFX5, RFKAP, or RFXANK, which are required for transcription of MHC-II, leading to lymphocytes (and other cell types) which lack MHC-II antigen presentation. Both Type I and Type II BLS lead to poor or nonexistent antigen presentation (via MHC-I or MHC-II) and immunodeficiency Both Type I and Type II BLS lead to poor or nonexistent antigen presentation (via MHC-I or MHC-II) and immunodeficiency (i.e. ‘immune ignorance’) [18], resulting in susceptibility to infections and early mortality

Methods

Results

Conclusion