Abstract 1514: Examining the impact of chromosomal instability on mucosal melanoma tumor infiltrate and responses to PD-1 based therapy
Authors: Armstrong Emma , Gottesdiener Lee , Schultz Nikolaus , Bakhoum Samuel F. , Hollmann Travis J. , Shoushtari Alexander 
Published: June 2022

Abstract
Mucosal melanoma (McM) is a rare subtype of melanoma arising from melanocytes of mucosal surfaces that comprises less than 2% of all melanomas in the US. Although PD-1 based checkpoint inhibition is standard initial therapy, McM has been shown to respond less often than cutaneous melanoma. We explored the hypothesis of this resistance being due to a lower tumor mutational burden (TMB) and high levels of chromosomal instability resulting in the formation of micronuclei, a greater than average fraction of genome altered (FGA) as defined by the MSK-IMPACT hybridization capture based NGS platform, and decreased immune infiltration. We utilized MSK-IMPACT data, to collect TMB and FGA data from 112 mucosal melanoma patients of which 56 had received frontline PD-1 based immunotherapy (28 a-PD-1 nivolumab/pembrolizumab, 28 nivolumab + ipilimumab). This population had a median follow-up time of 92 months, median progression free survival (PFS) of 13 months and median overall survival (OS) of 47 months. Dichotomized TMB was not associated with PFS or OS. However, higher than median FGA was associated with a significantly worse PFS (median 16 months vs. not reached [NR]) and OS (median 38months vs. NR). We then explored the association to traditional markers of chromosomal instability using multiplex immunofluorescence (IF) in tumor samples taken from 18 patients within the treatment cohort. We quantified cGMP-AMP synthase (cGAS) positive micronuclei present and found that FGA correlated directly with the number of micronuclei in the tumor, supporting that FGA is a reasonable indicator of chromosomal instability. As expected, there was no such association with micronuclei and TMB. Using multiplex IF we quantified CD8+ and CD8xPD1 co-positive cells at the tumor invading margin. Tumors with higher FGA had lower infiltration of CD8+ cells and CD8xPD1 co-positive cells. The same relationship was found when directly comparing number of micronuclei to CD8+ and CD8xPD1 co-positive cells. Our data suggests that patients with McM that harbor higher levels of chromosomal instability characterized by presence of micronuclei and resultant higher fraction of genome altered on MSK-IMPACT have fewer PD1+/CD8+ T cells in the tumor microenvironment and have inferior progression-free and overall survival with standard PD-1 blockade. This immunosuppressive mechanism may represent a uniquely poor prognosis group that may benefit from altering the downstream signaling resultant of chromosomal instability.
Citation Format: Emma Armstrong, Lee Gottesdiener, Nikolaus Schultz, Samuel F. Bakhoum, Travis J. Hollmann, Alexander Shoushtari. Examining the impact of chromosomal instability on mucosal melanoma tumor infiltrate and responses to PD-1 based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1514.