Characterization of the tumor immune microenvironment (TIME) and somatic landscape in gastrointestinal (GI) malignancies with MTAP deletions (del).

PRMT5 is a synthetic lethality target in patients (pts) with del and early phase trials are underway with PRMT5 inhibitors. Additionally, del are associated with a less immunogenic TIME and reduced efficacy of immunotherapy, but research has primarily not been focused on GI malignancies. Thus, we investigated the TIME and somatic landscape in GI malignancies with del. From the Tempus Database, we retrospectively analyzed de-identified next-generation sequencing data from pts across GI malignancies, including pancreatic (n=11,217), gastroesophageal (GEJ, n=5,803), cholangiocarcinoma (CCA, n=3,244), and colorectal (CRC, n=17,537) cancers. Tumors were sequenced with the Tempus xT DNA (648-gene panel) and xR RNA assays. del were defined as two-copy losses. Somatic alterations (alt), immune cell infiltration predicted from gene expression patterns, PD-L1 from IHC, TMB, and MSI were evaluated. Chi-squared/Fisher’s Exact tests or Kruskal-Wallis tests were used to assess statistical significance (p<0.05, q<0.05 for false discovery rate correction for multiple testing). del were identified in 14.8%, 11.3%, 0.9%, and 7.3% of pancreatic, CCA, CRC, and GEJ cancers, respectively. Of these, 98/93%, 99/91%, 92/89%, and 98/89% had co-occurring loss. In pancreatic, CCA, and CRC pts, del was associated with a reduced proportion of B cells and CD4 T cells, and there were higher percentages of macrophages vs pts with WT status (p<0.001 for all). Reductions in proportion of CD8 T cells were also associated with del in pancreatic and CCA pts (p<0.001 for both). Lower TMB (p=0.036) and MSI-H status (p=0.009) were found in CRC pts with del. GEJ with del also exhibited significantly lower MSI-H status than WT GEJ (p=0.014). , a marker of reduced immune infiltrates, were more prevalent in pts with del across GI malignancies (q<0.005). In the CCA cohort, there was a higher percentage of alt and FGFR2 fusions in pts with loss (q<0.001, q=0.028), while alt were higher in pancreatic cases with loss (q<0.001). This is the largest analysis of the TIME and somatic landscape of loss across GI malignancies. In pts with del and pancreatic cancer, CCA, and CRC, we observed a less immunogenic TIME pattern, indicating the evaluation of immunotherapy implications in these GI malignancies with del is warranted. Our findings are hypothesis-generating, providing further rationale to study synthetic lethality and novel combinatorial therapeutic strategies in GI malignancies with del.

Duke Scholars

Author John Strickler Medicine, Medical Oncology