Characterization of NY-ESO-1 gene expression in gastric cancer (GC).

person Annika Lenz Keck School of Medicine at USC, Los Angeles, CA info_outline Annika Lenz, Jia Zeng, Joanne Xiu, Sandra Algaze, Priya Jayachandran, Shivani Soni, Jae Ho Lo, Hiroyuki Arai, Wu Zhang, Pavel Brodskiy, Pat Gulhati, Benjamin Adam Weinberg, Emil Lou, Anthony Frank Shields, Richard M. Goldberg, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz, Evanthia T. Roussos Torres, Francesca Battaglin

Authors person Annika Lenz Keck School of Medicine at USC, Los Angeles, CA info_outline Annika Lenz, Jia Zeng, Joanne Xiu, Sandra Algaze, Priya Jayachandran, Shivani Soni, Jae Ho Lo, Hiroyuki Arai, Wu Zhang, Pavel Brodskiy, Pat Gulhati, Benjamin Adam Weinberg, Emil Lou, Anthony Frank Shields, Richard M. Goldberg, John Marshall, Wolfgang Michael Korn, Heinz-Josef Lenz, Evanthia T. Roussos Torres, Francesca Battaglin Organizations Keck School of Medicine at USC, Los Angeles, CA, Caris Life Sciences, Phoenix, AZ, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, USC Keck School of Medicine, Los Angeles, CA, Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, Masonic Cancer Center/ University of Minnesota School of Medicine, Minneapolis, MN, Karmanos Cancer Institute, Wayne State University, Detroit, MI, Department of Medicine, West Virginia University, Morgantown, WV, Georgetown University, Washington, DC, Division of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA Abstract Disclosures Research Funding Other Background: Tumor specific antigens, such as NY-ESO-1 , are emerging as key tumor immune modulating factors with great potential to be used as therapeutic targets to enhance immunotherapy efficacy and expand treatment options for GC. We sought to compare GC tumors expressing high vs low levels of NY-ESO-1 in terms of immune cell abundance in the tumor microenvironment (TME) as well as distinct molecular features and immune biomarkers. Methods: 1967 tumor samples tested with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS) by Caris Life Sciences (Phoenix, AZ) were retrospectively reviewed. The top quartile of transcripts per million was considered high while the bottom quartile was considered low NY-ISO-1 expression. Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations. Mismatch repair deficiency/microsatellite instability (dMMR/MSI) status was evaluated by a combination of IHC, fragment analysis and NGS of known MSI loci. Gene fusions were detected based on WTS. X 2 , Fisher-exact, and Mann Whitney tests were used for comparison and significance adjusted for multiple testing by Benjamini-Hochberg correction ( q < 0.05). Cell infiltration in the TME was estimated by quanTIseq. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy (T cell-inflamed signature: TIS). Results: The analysis was focused on primary tumors (N = 1323) in this initial study. Expression of NY-ESO-1 was lower in primary/local than metastases (Fold Change FC met vs primary: 1.60, q < 0.05). NY-ESO-1 expression did not appear to be strongly associated with distinct gene mutation profiles in GC. There were no significant differences between low and high expression of NY-ESO-1 with regards to well established immuno-oncology markers (dMMR/MSI, TMB, PD-L1). However, high NY-ESO-1 expression was positively associated with immune related gene expression including CD274 , CD80 , CD86 , CTLA4 , HAVCR2 , IDO1 , IFNG , LAG3 , PDCD1 , and PDCD1LG2 (FC low vs high: 0.56 to 0.79, q < 0.0001). High NY-ESO-1 expression was also positively associated with cell abundance in the TME including NK cells (FC = 0.87, q < 0.0001), monocytes (FC = 0.29, q < 0.05), myeloid dendritic cells (FC = 0.66, q < 0.0001), CD4+ non-reg T cells (FC = 0.54, q < 0.0001), and CD8+ T cells (FC = 0.73, q < 0.05). Similarly, tumors with high NY-ESO-1 expression were associated with higher TIS scores ( q < 0.0001). Conclusions: In our large cohort of GC, tumors expressing high NY-ESO-1 displayed a distinct landscape of immune cells in the TME and were associated with high expression of immune related genes, as well as high TIS score, which has been reported to predict benefit from anti-PD-1 treatment. The results of our analysis support an association between a more immunologically active tumor microenvironment and NY-ESO-1 gene expression which may have relevant implications on immunotherapy treatment for GC.