Strength of immune selection in tumors varies with sex and age

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Individual human leukocyte antigen (MHC) genotype influences tumor mutation patterns.
• Immune checkpoint inhibitors (ICIs) benefit only a subset of patients (~30%).
• Poorer ICI response rates are observed in younger and female patients, but the underlying mechanisms are unclear.

Purpose of the Study:

• To investigate the role of MHC-based immune selection in sex and age-related differences in tumor mutational landscapes.
• To determine if MHC-based selection impacts the presentation of driver mutations and subsequent response to immunotherapy.

Main Methods:

• Analysis of tumor mutational data stratified by patient age and sex.
• Assessment of MHC-based selection pressures on driver mutations.
• Comparison of mutation presentation and immune selection strength across demographic groups.

Main Results:

• Tumors in younger and female patients accumulate more poorly presented driver mutations compared to older and male patients.
• Younger patients exhibit stronger MHC-based driver mutation selection.
• Younger females show compounded effects, with significantly higher MHC-II-based selection.

Conclusions:

• Tumor immune selection strength during tumorigenesis is influenced by patient sex and age.
• Differential immune selection may affect the repertoire of mutant peptides presented by tumors.
• This variability could explain differences in response rates to immune checkpoint inhibitor therapy.