Strength of immune selection in tumors varies with sex and age

Andrea Castro,Hannah Carter,Maurizio Zanetti,Wesley Kurt Thompson,Ludmil B Alexandrov,Rachel Marty Pyke,Xinlian Zhang,Chi-Ping Day

doi:10.1038/s41467-020-17981-0

Abstract

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.

Highlights

Individual major histocompatibility complex (MHC) genotype constrains the mutational landscape during tumorigenesis
Patient Harmonic-mean Best Rank (PHBR)-I and -II scores were calculated for all patients across the 1018 driver events by taking the harmonic mean of each allele’s best NetMHCpan percentile rank affinity score, providing an estimate of each patient’s potential to present each mutation via MHC-I and MHC-II, respectively
We found that younger and female patients accumulate driver mutations in their tumors that are less readily presented by their MHC molecules (Fig. 5), suggesting a stronger toll by immune selection early in tumorigenesis

Summary

Introduction

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. 1234567890():,; The major histocompatibility complex (MHC) exposes protein content on the cell surface to allow detection of antigens by the immune system This applies to nonself antigens such as viral proteins, and self-proteins that include tumor antigens. A recent study has found sex-based differences in molecular biomarkers and immune checkpoint expression in multiple tumor types treated with ICB8. These studies suggest that these differences are sex-specific and not lifestyle dependent

Methods

Results

Conclusion