Abstract 2242: KRAS mutations suppress the tumor immune microenvironment in colorectal cancer

Abstract

Abstract Background: KRAS mutations (KRASmut) drive tumorigenesis through various signaling pathways that are associated with worse survival in colorectal cancer patients (CRC). Immune evasion is a hallmark of KRAS-driven cancer, but the role of KRASmut in the regulation of the immune response is unclear, particularly in the tumor microenvironment (TME), which often assists cancer cells to thrive and successfully escape immune surveillance. Here, we explore the immunobiological impacts of KRASmut in CRC patients. Methods: A total of 97 fresh frozen tumor samples were collected from each CRC patient with stage I-IV who underwent surgical treatment at the Department of Surgery, Faculty of Medicine Siriraj Hospital between October 2010 and March 2011. First, all patients were identified KRAS mutational status and compared overall survival (OS) with wild-type KRAS (KRASwt). Next, we analyzed the gene expression profiling of KRASmut which was performed using the Nanostring platform. Finally, we performed the biological network analysis focusing on immunological pathways associated with KRASmut using the Ingenuity Pathway Analysis (IPA). Results: We observed KRASmut in 41.24% (n=40) of the total cases. Mutations occurred primarily in exon 2 (total n=36; codon 12, n=28; codon 13, n=8) and rarely in exon 3 (n=4). Patients with KRASmut CRC in exon 2 and exon 3, showed significantly worse OS compared to KRASwt (HR 1.77, 95% CI 1.07-2.93; P<0.05). Comparing gene expression profiles between KRASmut and KRASwt, found that the survival outcome of patients with KRASmut was correlated with immunosuppressive TME by activation of genes encoded in TGFβ signaling pathway. In addition to activating TGFβ pathway, the gene expression profile of KRASmut also interrupted gene encoded pro-inflammatory cytokines, including TNFRSF12, IRF6, CCR2, CCL8, CCL11, CXCR3 and CXCL10. IPA analysis revealed that differentially expressed genes of KRASmut were significantly enriched in regulation of epithelial mesenchymal transition (EMT) and macrophage-stimulating protein receptor d'origine nantais (MSP-RON) signaling pathways (P value<0.001), which are strongly associated with maintaining the stability of the TME and contributing to immune escape in the immune TME. Conclusions: Our results suggested that KRASmut activated TGFβ and interrupted pro-inflammatory cytokine to suppress tumor immune microenvironment in CRC. Future studies and clinical trials in patients with CRC with KRASmut should take these transcriptional profiles into account. Citation Format: Pariyada Tanjak, Amphun Chaiboonchoe, Tharathorn Suwatthanarak, Onchira Acharayothin, Kullanist Thanormjit, Jantappapa Chanthercrob, Thanawat Suwatthanarak, Bundit Wannasuphaphol, Kemmapon Chumchuen, Bhoom Suktitipat, Somponnat Sampattavanich, Krittiya Korphaisarn, Ananya Pongpaibul, Naravat Poungvarin, Harald Grove, Woramin Riansuwan, Atthaphorn Trakarnsanga, Asada Methasate, Manop Pithukpakorn, Vitoon Chinswangwatanakul. KRAS mutations suppress the tumor immune microenvironment in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2242.