Abstract 652: Tumor cell-specific IL-1/IL-1R signaling promotes KRAS mutant lung tumorigenesis
Authors: Krishna Avantika , Clowers Michael J. , Yuan Bo , Mutala Milind , Sancristobal Maria Jose Arredondo , Colunga Jocelynn , De Maleki Ryan , Phan Linda , Kadara Humam , Moghaddam Seyed Javad 
Published: April 2023

Despite improved diagnosis and treatment strategies such as immunotherapy, lung cancer is still the leading cause of cancer-related deaths worldwide in both men and women. Lung adenocarcinoma (LUAD) with driver mutations in the KRAS oncogene is the most prevalent molecular subtype of lung cancer. KRAS mutant LUAD exhibits aggressive biology in part due to enhanced pro-tumor inflammation mediated by activation of the nuclear factor-κB (NF-κB) and, consequently, elevated expression of various cytokines. While the pro-inflammatory cytokine IL-1β is a product of the NF-κB pathway it also acts as a potent activator, further amplifying the production of protumor cytokines via a positive feedback loop. We have shown that IL-1β blockade enhances anti-tumor immune responses while inhibiting immunosuppression in a mouse model of KRAS mutant LUAD driven by lung epithelial cell-specific expression of KRASG12D (CCSPCre/LSL-KRASG12D, CC-LR mouse). Cell lineage-specific mechanisms that underlie these anti-tumor effects following inhibition of IL-1β are still poorly understood. To fill this void, we here explored the effects of targeting the IL-1R receptor in KRAS mutant lung epithelial cells in the CC-LR mouse model. We studied tumor development and host immune response in 14-week-old CC-LR mice with conditional knockout of IL-1R in KRAS mutant lung epithelial cells (LR/IL-1RΔ/Δ) in comparison to age- and sex-matched control CC-LR littermates. LR/IL-1RΔ/Δ mice displayed markedly reduced tumor multiplicity (~50%) when compared to control CC-LR mice concomitant with decreased cell proliferation and angiogenesis evidenced by attenuated immunohistochemical expression of Ki-67 and ERG. Flow cytometry analysis showed an elevated inflammatory response, most evidently seen through the significant increase in infiltrating monocytes. Interestingly, a shift in type-1 conventional dendritic cells, commonly involved in antigen-cross presentation in tumorigenesis, to type-2 conventional dendritic cells was seen in LR/IL-1RΔ/Δ mice, suggesting a different method of cross-presentation resulting from the conditional knockout of IL-1R that could potentially lead to a protective T-cell response. These results were further confirmed via gene expression analysis of respective markers. Our findings provide further support for the role of the IL-1 cytokine family in the development and progression of KRAS mutant LUAD as well as warrant further studies targeted towards understanding the mechanistic effects IL-1β has on the tumor microenvironment.

Citation Format: Avantika Krishna, Michael J. Clowers, Bo Yuan, Milind Mutala, Maria Jose Arredondo Sancristobal, Jocelynn Colunga, Ryan De Maleki, Linda Phan, Humam Kadara, Seyed Javad Moghaddam. Tumor cell-specific IL-1/IL-1R signaling promotes KRAS mutant lung tumorigenesis [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 652.