Immune Selection in Younger, Female Patients May Affect Driver Mutations

Both sex and age may influence immune selection in tumors, with younger and female patients showing enhanced potential for immune evasion based on driver mutations within tumors, according to study results published in Nature Communications.

The researchers explained in their report that sexual dimorphism and age appear to affect immune responses to tumors and the efficacy of immune checkpoint inhibitor therapies against tumors. They noted that female and younger patients show less favorable patterns, even though these demographic groups may otherwise tend to have strong immune responses.

The research team had previously developed a model to predict the ability of a patient’s major histocompatibility complexes (MHCs) to recognize peptides arising from particular tumor mutations, and they applied the model to this study.

In the current study, the research team from the University of California San Diego in La Jolla set out to determine whether age or sex have associations with MHC-oriented selection of mutations by tumors, as a pathway to immune evasion by tumors.

The researchers performed human leukocyte antigen (HLA) genotyping on whole exome sequencing-based patient data available from The Cancer Genome Atlas. HLA genotypes were analyzed to estimate the ability of patients’ MHCs to present particular residues, which was quantified as a Patient Harmonic-mean Best Rank (PHBR) score.

The researchers identified a set of 1018 suspected driver mutations and developed models to evaluate whether PHBR scores, sex, or age may predict the probability of mutations.

Overall, there did not appear to be differences by sex or age in the capacity of MHC molecules to present residues from driver mutations. Amounts of driver mutations were also not observed to differ based on age or sex.

However, analyses of PHBR scores against mutations present in patients suggested that female patients showed less potential than male patients to present the residues from their driver mutations by either MHC-1 (P <2.6 × 10^-4) or MHC-2 (P <1.2 × 10^-7). Younger patients showed similar disadvantages (P <2.4 × 10^-5 for MHC-1 analysis, and P <7.3 × 10^-4 for MHC-2 analysis). These sex- and age-specific analyses were performed with data from up to 2900 and 3928 patients, respectively.

Additionally, interactions between PHBR scores and the probability of mutations indicated that female and younger patients in this analysis showed stronger immune selection. The researchers interpreted the study’s results to suggest that the driver mutations that persist in younger and female patients may be less immunogenic and that this may impact patient response to immune checkpoint blockade.

“In conclusion, this study indicates that immune selection exerts its toll differently with respect to sex and age, with a greater effect in younger females,” the authors wrote.

Reference

Castro A, Pyke RM, Zhang X, et al. Strength of immune selection in tumors varies with sex and age. Nat Commun. 2020;11(1):4128. doi:10.1038/s41467-020-17981-0