LAUSR

Background: CEACAM6 is a cell adhesion receptor of the Ig-family over-expressed exclusively in primates and human pancreatic ductal adenocarcinoma (PDA). It is present in all subtypes and is enriched classical activated stroma subtype. CEACAM6 has multifaceted roles in KRAS mutant PDA and is a poor prognostic maker (Pandey et al. Sci Rep 2019). We report here in PDA, high CEACAM6 modulates the tumor microenvironment with an immunosuppressive landscape. Methods: RNA-Seq data of PDA patient samples from TCGA and GEO were obtained, normalized and log transformed for analysis. Tumor samples were stratified into cohorts of high and low CEACAM6. Pearson correlation coefficient is utilized to identify CEACAM6 correlated genes and enrichment of signaling pathways. The two cohorts were scored by ESTIMATE for stromal and immune population. Abundance of different cell populations were calculated utilizing MCPcounter and ConsensusTME methods. All analysis was performed using R (v 4.3). Results: High CEACAM6 PDA samples had both stromal and immune components. Half of the high expressing samples had a higher immune score vs stromal score. The other half had both high or both low, immune and stromal score. Investigating the immune genes that are utilized for scoring, we found several immune genes differentially expressed in high CEACAM6 (up-regulated genes - ADAM8, IL2RG, LYZ, SELPLG involved in innate immunity) compared to low CEACAM6 samples. Genes under expressed in high CEACAM6 samples were CD27, NKG7, IL18RAP, LILRB1, KLKRK1 involved in promoting immune response and cell protection. Overall TCGA PDA samples have lower enrichment of immune cells compared to higher enrichment of fibroblasts, endothelial cells, macrophages, monocytes and dendritic cells. The NK cells are overall low in PDA but enriched in some lower CEACAM6 samples. Plasma cells, B-cells, CD8 cells, NK cells, Cytotoxic T-cells, Tγδ-cells have very poor representation in higher CEACAM6 samples but present in some low CEACAM6 expressing samples. Some of the TCGA PDA samples have T-reg cells but high CEACAM6 do not enrich of T-reg cells. High CEACAM6 samples are enriched for metabolic pathways. Conclusions: CEACAM6 over-expressed in PDA have pathologic functions which include reshaping the stroma, suppressing host immunity and inhibiting apoptosis. An anti-CEACAM6 Mab increases apoptosis, necrosis and anti-tumor activity in PDA. Citation Format: Ritu Pandey, Yuliang Chen, Mihir Patil, Patrick J. Conway, Aisha Al-Khinji, Daruka Mahadevan. Over-expression of CEACAM6 negatively modulates the tumor microenvironment in pancreatic cancer [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 3156.