Sex-specific differences in immunogenomic features of response to immune checkpoint blockade.

Introduction: The magnitude of response to immune checkpoint inhibitor (ICI) therapy may be sex-dependent, as females have lower response rates and decreased survival after ICI monotherapy. The mechanisms underlying this sex dimorphism in ICI response are unknown, and may be related to sex-driven differences in the immunogenomic landscape of tumors that shape anti-tumor immune responses in the context of therapy.
Methods: To investigate the association of immunogenic mutations with HLA haplotypes, we leveraged whole exome sequence data and HLA genotypes from 482 non-small cell lung cancer (NSCLC) tumors from The Cancer Genome Atlas (TCGA). To explore sex-specific genomic features linked with ICI response, we analyzed whole exome sequence data from patients with NSCLC treated with ICI. Tumor mutational burden (TMB), HLA class I and II restricted immunogenic missense mutation (IMM) load, and mutational smoking signature were defined for each tumor. IMM load was combined with HLA class I and II haplotypes and correlated with therapeutic response and survival following ICI treatment. We examined rates of durable clinical benefit (DCB) for at least six months from ICI treatment initiation. Findings were validated utilizing whole exome sequence data from an independent cohort of ICI treated NSCLC.
Results: Analysis of whole exome sequence data from NSCLC tumors of females and males revealed that germline HLA class II diversity (≥9 unique HLA alleles) was associated with higher tumor class II IMM load in females (p=0.01) and not in males (p=0.64). Similarly, in tumors of female patients, somatic HLA class II loss of heterozygosity was associated with increased IMM load (p=0.01) while this association was not observed in tumors in males (p=0.20). In females, TMB (p=0.005), class I IMM load (p=0.005), class II IMM load (p=0.004), and mutational smoking signature (p<0.001) were significantly higher in tumors responding to ICI as compared to non-responding tumors. In contrast, among males, there was no significant association between DCB and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017).
Conclusions: Inherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICI and likely mediate the dimorphic outcomes with ICI therapy. Deeper understanding of the selective pressures and mechanisms of immune escape in tumors in males and females can inform patient selection strategies and can be utilized to further hone immunotherapy approaches in cancer.
Competing Interests: VA receives research funding to the institution from Astra Zeneca and has received research funding to her institution from Bristol-Myers Squibb in the past 5 years. SS has served in a consulting role for Genentech/Roche. KM has received research funding to the institution from Mirati and Bristol Myers Squibb, and she has served in a consulting role for Amgen, Janssen, Mirati, AstraZeneca and Puma. VL has received research funding to the institution from GlaxoSmithKline, Bristol Myers Squibb, Merck, and SeaGen and he has served in a consulting role for Takeda, SeaGen, Bristol Myers Squibb, AstraZeneca, Guardant Health and Takeda. JM has received research funding to the institution from Merck via the Conquer Cancer Young Investigators Award, and has served in a consulting role for MJH Life Sciences, Johnson & Johnson, and Doximity. JF has received research funding to the institution from AstraZeneca, Pfizer, and Bristol Myers Squibb, and has served in a consulting role for Genentech/Roche, Eli Lilly, AstraZeneca, Merck, Takeda, Coherus, Regeneron, and Pfizer. BL has served in a consulting role for AstraZeneca, Daiichi Sankyo, Janssen, Pfizer, Amgen, Takeda, Genentech/Roche, Eli Lilly, Mirati Therapeutics, and Guardant. DE has served in a consulting role for Beyond Spring Pharmaceuticals. CH has received research funding to the institution from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, and GlaxoSmithKline, and has served in a consulting role for AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Jannsen and GlaxoSmithKline. JB has received research funding to the institution from AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics Inc and Revolution Medicines, has served in a consulting role for Amgen, AstraZeneca, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron, and is in the Data and Safety Monitoring Board/Committees of GlaxoSmithKline and Sanofi. PF has received research funding to the institution from AstraZeneca, Bristol Myers Squibb, Novartis, Corvus, Kyowa, and has served as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Iteos, Janssen, and as a data safety monitoring board member for Polaris and Flame Therapeutics. JN has received research funding from MSD, AstraZeneca, Bristol Myers Squibb, Amgen, Genentech/Roche, Novartis, has served in a consultant/advisory role for Merck, MSD, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Pfizer, Takeda, Daiichi Sankyo, Kaleido Biosciences, Amgen and Mirati Therapeutics, and is in the Data and Safety Monitoring Board/Committee of Daiichi Sankyo. Under a license agreement between Genentech and the Johns Hopkins University, XS and RK and the University are entitled to royalty distributions related to technology described in the study discussed in this publication. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.
(Copyright © 2022 Scott, Shao, Niknafs, Balan, Pereira, Marrone, Lam, Murray, Feliciano, Levy, Ettinger, Hann, Brahmer, Forde, Karchin, Naidoo and Anagnostou.)