Landscape of innate and adaptive immunity targets in oesophagogastric adenocarcinoma (OGA).

Abstract

4063 Background: Anti-PD-1 therapy modestly improves survival in chemorefractory OGA. Combining PD-1 blockade with novel checkpoint inhibitors, T-cell co-stimulatory molecules, or myeloid suppressors could enhance PD-1 inhibition. Herein, we explore the landscape of known targetable immune markers in non-Asian OGA. Methods: OGA patient biopsies were prospectively collected and clinically annotated from 19 UK cancer centres (Oesophageal Cancer Clinical and Molecular Stratification – OCCAMs network). Genomic (WGS) and transcriptomic (bulk-RNA seq) data were generated using Illumina and processed using a validated in-house pipeline (Frankell, Nat Genetics 2019). Gene expression was computed in transcripts per kilobase. Using unsupervised clustering patient clusters were selected according to the expression of gene targets for immune therapy - PD-L1, LAG3, TIM3, TIGIT, ICOS, CCR2, CCR5, CXCR4, and CSF1R. Immune cell infiltration was extrapolated using GSVA gene set enrichment analysis. Results: RNAseq data were available for 251 patients; 96% had operable tumours (Stage I: 6%, II: 63%, III: 22%, IV: 4%). In untreated patients (n = 156) 3 subgroups were identified: immune low (83, 53%) with low level expression of all 9 markers, immune high (14, 9%) with high expression of all or majority of markers and intermediate (59, 38%) with heterogenous marker expression. Clinicopathological variables (sex, age, smoking, tumour location (gastric/GEJ/esophagus) and tumour regression grade) were similarly distributed across subgroups. In a cohort of 114 patients with matched WGS and RNAseq data tumour mutation burden was not different between subgroups. In post-chemotherapy biopsies (n = 95) a similar co-expression pattern was observed. Gene enrichment analysis supported infiltration by cells of innate and adaptive immune system in immune high patients. Neoantigen results, phenotypic immunohistochemistry and optimised survival outcomes according to lymphoid and myeloid target expression will be presented. Conclusions: High level co-expression of immune regulatory targets in OGA patients may limit the efficacy of anti-PD-1 monotherapy. Combination immune directed therapies may be required in this patient group.