Abstract 1617: Sex-specific genomic determinants of response to immunotherapy
Authors: Scott Susan C. , Shao Xiaoshan M. , Niknafs Noushin , Balan Archana , Lanis Mara , White James , Forde Patrick , Marrone Kristen , Lam Vincent , Feliciano Josephine , Levy Benjamin , Brahmer Julie , Ettinger David , Velculescu Victor , Karchin Rachel , Hann Christine , Naidoo Jarushka , Anagnostou Valsalmo 
Published: July 2021

Abstract
Introduction: The magnitude of benefit from immune checkpoint inhibitors (ICI) may be sex-dependent, however the mechanisms underlying this sex dimorphism in ICI response are unknown.
Methods: To explore sex-specific genomic features linked with ICI response, we analyzed whole-exome sequence data of 89 patients with non-small cell lung cancer (NSCLC) treated with ICI. Sequence alteration, mutation signatures and clonality analyses were combined with HLA class I and II genotyping, and computationally derived mutation-associated neoantigens were evaluated based on the peptide-HLA binding affinity (&lt;500nM) and the relative binding affinity between mutated and wild-type peptides [quotient differential aggretopic index (qDAI) &gt;2]. Missense sequence alterations were characterized as putatively immunogenic mutations (IMM), and HLA class I and II matched IMM loads were calculated. Durable clinical benefit ≥6 months was used to define response. Our findings were validated in an independent cohort of ICI treated NSCLC (n=34).
Results: There were no differences in the genomic features assessed or in clinical outcomes between male (n=46) and female (n=43) patients. Female responders had higher tumor mutational burden (TMB; p=0.004), in contrast to male patients (p=0.15). Similarly, a mutation spectra-derived smoking signature was associated with response in females (p=0.001) but not in males (p=0.2). Responding female patients had a more clonal TMB compared to non-responders (p=0.008). Importantly, female responders harbored a significantly higher class I and II IMM load (p=0.008 and p=0.004 respectively), which was not appreciated in males. These findings were supported by analyses of a second independent cohort, where HLA class I and II IMM load differentiated responders from non-responders only in the female patient group (p=0.008 and p=0.004 for class I and II IMM, respectively). In the primary cohort, germline HLA class I zygosity was not associated with outcome for either sex, however a trend towards HLA DQ-B1 homozygosity and worse outcome was evident only in females. Importantly, when HLA class II diversity was combined with class II IMM load, a survival benefit was noted for tumors harboring a high IMM load and maximal HLA II germline diversity in males (log rank p=0.015) but not in females. Similarly, HLA class I diversity was important in males when combined with class I IMM load, such that low IMM load combined with reduced antigen presentation capacity was predictive of non-durable clinical benefit (p=0.003 vs p=0.68 for males and females respectively) and was linked with shorter overall survival (log rank p= 0.062 vs p=0.58 for males and females respectively).
Conclusions: Our findings support a sex dimorphism in the genomic determinants of response to immune checkpoint blockade, which may point to differences in immune surveillance between males and females in the context of therapy and may be used to tailor therapeutic delivery.
Citation Format: Susan C. Scott, Xiaoshan M. Shao, Noushin Niknafs, Archana Balan, Mara Lanis, James White, Patrick Forde, Kristen Marrone, Vincent Lam, Josephine Feliciano, Benjamin Levy, Julie Brahmer, David Ettinger, Victor Velculescu, Rachel Karchin, Christine Hann, Jarushka Naidoo, Valsalmo Anagnostou. Sex-specific genomic determinants of response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1617.