Abstract 7522: Association between the CNTN4 expression and responsiveness to pembrolizumab in gastric cancer

Abstract Even though numerous strategies for controlling malignant tumors have been established with immunotherapies, a solution for non-favorable responses to immunotherapy is still unclear. To address this unsolved problem, we previously suggested that a new immune checkpoint, CNTN4, is expressed on the tumor side and suppresses T cell-dependent immune activation. We further investigated the association between the clinical outcome of pembrolizumab and the expression of CNTN4 in the gastric cancer cohort using bulk RNA sequencing data to establish a clinical strategy for targeting CNTN4. We split the patients into high- or low-group based on the expression of CNTN4 and CD274 (PD-L1) with the median of those two genes and analyzed for the responses. As a result, patients who had low-CNTN4 expression and high-CD274 expression were favorable to the pembrolizumab (Objective response rate, ORR; 64.3% [9/14]). However, patients who had high-CNTN4 expression and high-CD274 expression showed unfavorable responses (ORR; 0% [0/9]. Ꭓ2 = 5.951, P = 0.002). We also figured out that non-responders (NRs, N = 33) had a relatively lower expression of CD274 (p = 0.0012) and a higher expression of CNTN4 (p = 0.0015) compared to responders (Rs, N =12). Furthermore, in CD274-high patients, NRs showed significantly higher CNTN4 expression than Rs (Fold change = 2.17. P = 0.0086). Immune-related cytokine genes, such as IFNG, GZMA, and CXCL9, were negatively correlated to CNTN4 expression (R = -0.69, P = 2 × 10−4; R = -0.52, P = 0.0108; R= -0.54, and P = 0.0077, respectively.). In addition to the cancer cells, cancer-associated fibroblast, important for immunotherapy, was deconvoluted from bulk RNA data and showed higher CNTN4 expressions in NRs than Rs (Fold change = 3.3, P = 0.002). When classifying tumor tissue based on TCGA molecular subtypes, genomically stable (GS) type and chromosomal instability (CIN) were more observed in the NRs compared to the Rs with poor prognosis. CIN and GS type patients showed higher CNTN4 and lower CD274 expression than other TCGA subtypes. We also figured out that all CNTN4-high patients were composed of CIN or GS types. Similarly, higher CNTN4 expression and lower CD274 expression were observed in CIN and GS gastric patients from the TCGA database. Moreover, overall survival (OS) and progression-free survival (PFS) were poorer in CNTN4-high patients (OS: median of CNTN4-high = 9.73 [95% CI= 4.77-NA] months, median of CNTN4-low = NA [95% CI= 9.03-NA] months, P = 0.072. Hazard ratio = 2.15 [95% CI = 0.917-5.037], P = 0.078) (PFS: median of CNTN4-high = 2.10 [95% CI= 1.33-3.97] months, median of CNTN4-low = 5.47 [95% CI= 2.80-NA] months, P = 0.0004. Hazard ratio = 3.303 [95% CI = 1.647-6.624], P = 0.0008).Together, we suggest that CNTN4 is a potential ICP candidate for gastric cancer patients unfavorable to pembrolizumab treatment. The anti-CNTN4 antibody GENA-104A16 is under the IND submission stage for clinical studies. Citation Format: Mi Young Cha, Gihyeon Kim, Changho Park, Bu-Nam Jeon, Kyung Mi Park, Hansoo Park, Chan-Young Ock. Association between the CNTN4 expression and responsiveness to pembrolizumab in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7522.