In-Silico Analysis of The Correlation Between PD-L1 and ProInflammatory Type Interleukins and The Distribution of Their Potential Primary Sources in KRAS-Mutated Non-Small Cell Lung Carcinoma

Objective: Non-Small Cell Lung Cancer has a high incidence and great clinical importance as the cancer subtype with the highest mortality. It is necessary to investigate cytokines associated with the Programmed death-ligand 1, one of the immunotherapeutic target molecules, in KRas mutant lung cancer cells. Materials and Methods: In this study, the expression of Programmed death-ligand 1 as well as pro-inflammatory interleukins was evaluated in 44 lung cancer cell lines harboring KRas mutations and RNAseq expression data of lung adenocarcinoma patients and correlation analyses were performed. Macrophages and dendritic cells, the major immune cells associated with Interleukin-1, Interleukin-6, Interleukin-12 and Interleukin-23, were also evaluated. Results: In KRas mutant lung cancer cells and lung adenocarcinoma tissues, expression of cytokines Interleukin-1A, Interleukin-6, Interleukin-12 and Interleukin-23 showed a positive correlation with Programmed death-ligand 1 expression (p≤0.05). The quantity of M1 macrophages and dendritic cells, both of which are cytokine-producing immune cells, is less in KRas mutant lung cancer tissues than nonmutants. Conclusion: Detailed studies in clinical samples, especially in blood, primary, and metastatic tissues, will help to create and validate cytokine panels that can be used in therapeutic targeting of KRas mutant subtype lung cancer with high Programmed death-ligand 1 expression.

PDF

___

[1] Carioli G, Bertuccio P, Boffetta P, et al. European cancer mortality predictions for the year 2020 with a focus on prostate cancer. Ann Oncol. 2020; 31(5): 650-658.
[2] Inamura K. Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification. Front Oncol. 2017; 7: 193.
[3] Westcott PM, To MD. The genetics and biology of KRAS in lung cancer. Chin J Cancer. 2013; 32(2): 63-70.
[4] Ghimessy A, Radeczky P, Laszlo V, et al. Current therapy of KRAS-mutant lung cancer. Cancer Metastasis Rev. 2020.
[5] Mohsen N, Ahmadreza S, Fatemeh H, et al. Frequency of K-RAS and N-RAS Gene Mutations in Colorectal Cancers in Southeastern Iran. Asian Pac J Cancer Prev. 2016; 17(9): 4511-4515.
[6] Juneja VR, McGuire KA, Manguso RT, et al. PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med. 2017; 214(4): 895-904.
[7] Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity. 2018; 48(3): 434-452.
[8] Yu H, Boyle TA, Zhou C, et al. PD-L1 Expression in Lung Cancer. J Thorac Oncol. 2016; 11(7): 964-975.
[9] Chen J, Jiang CC, Jin L, et al. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol. 2016; 27(3): 409-416.
[10] Chen S, Crabill GA, Pritchard TS, et al. Mechanisms regulating PD-L1 expression on tumor and immune cells. J Immunother Cancer. 2019; 7(1): 305.
[11] Liu C, Zheng S, Jin R, et al. The superior efficacy of antiPD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 2020; 470: 95-105.
[12] Falk AT, Yazbeck N, Guibert N, et al. Effect of mutant variants of the KRAS gene on PD-L1 expression and on the immune microenvironment and association with clinical outcome in lung adenocarcinoma patients. Lung Cancer. 2018; 121: 70-75.
[13] Chen N, Fang W, Lin Z, et al. KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother. 2017; 66(9): 1175-1187.
[14] Golay HG, Barbie DA. Targeting cytokine networks in KRAS-driven tumorigenesis. Expert Rev Anticancer Ther. 2014; 14(8): 869-871.
[15] Ancrile B, Lim KH, Counter CM. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 2007; 21(14): 1714-1719.
[16] Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumorinfiltrating immune cells. Nucleic Acids Res. 2020; 48(W1): W509-W514.
[17] Li T, Fan J, Wang B, et al. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21): e108-e110.
[18] Li B, Severson E, Pignon JC, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol. 2016; 17(1): 174.
[19] Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5): 453-457.
[20] Yang H, Liang SQ, Schmid RA, et al. New Horizons in KRASMutant Lung Cancer: Dawn After Darkness. Front Oncol. 2019; 9: 953.
[21] McCormick F. KRAS as a Therapeutic Target. Clin Cancer Res. 2015; 21(8): 1797-1801.
[22] Lan B, Ma C, Zhang C, et al. Association between PD-L1 expression and driver gene status in non-small-cell lung cancer: a meta-analysis. Oncotarget. 2018; 9(7): 7684-7699.
[23] Coelho MA, de Carne Trecesson S, Rana S, et al. Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA. Immunity. 2017; 47(6): 1083- 1099 e1086.
[24] Mandai M, Hamanishi J, Abiko K, et al. Dual Faces of IFNgamma in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity. Clin Cancer Res. 2016; 22(10): 2329-2334.
[25] Chan LC, Li CW, Xia W, et al. IL-6/JAK1 pathway drives PDL1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest. 2019; 129(8): 3324-3338.
[26] Caetano MS, Zhang H, Cumpian AM, et al. IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer. Cancer Res. 2016; 76(11): 3189-3199.
[27] Unver N, Delgado O, Zeleke K, et al. Reduced IL-6 levels and tumor-associated phospho-STAT3 are associated with reduced tumor development in a mouse model of lung cancer chemoprevention with myo-inositol. Int J Cancer. 2018; 142(7): 1405-1417.
[28] Langrish CL, McKenzie BS, Wilson NJ, et al. IL-12 and IL23: master regulators of innate and adaptive immunity. Immunol Rev. 2004; 202: 96-105.
[29] Lim KS, Yong ZWE, Wang H, et al. Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells. J Biol Chem. 2020; 295(19): 6387-6400.