KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Abstract

Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

“…The relationship between the immune system and pancreatic cancer development is complex. Pancreatic inflammation, including immune cell infiltration associated with pancreatitis, can promote the initiation of pancreatic cancer lesion formation [39,49], while subsequent growth and progression of Kras G12D -driven pancreatic cancer are supported by the recruitment of immune cells that generate a permissive, immunosuppressive tumor microenvironment [50][51][52]. Therefore, we assessed the effect of loss of Prkci expression on infiltrating immune cells in Kras G12D -driven dysplastic pancreatic lesions.…”

Mutant KRAS-Associated Proteome Is Mainly Controlled by Exogenous Factors

“…MutKRAS cancer cells orchestrate a pro-tumorigenic microenvironment [14][15][16][17]27]. Though, whether and how tumor microenvironment-derived signals affect mutKRAS signaling and the subsequent impact on cancer cells response has been overlooked.…”

Modulation of fibroblasts phenotype by colorectal cancer cells-secreted factors is mostly independent of oncogenic KRAS

“…The effect of mutKRAS on the regulation of the tumor immune microenvironment is one of the most well described noncancer cell effect. Specifically, mutKRAS immunomodulator effects, have been reported to occur at the level of recruitment, activation, and differentiation of immune cells, supporting the immune compartment protumorigenic roles, and cancer cell evasion from immunosurveillance [6][7][8][9][10][11]13 . The effects of mutKRAS on the modulation of fibroblasts and cancer associated fibroblasts (CAFs) phenotypes are not so well studied and the majority of the available studies are focused on pancreatic cancer 6,7 .…”

“…Adding to the roll of key cancer activities controlled by mutKRAS, it has been shown that its oncogenic signaling extends beyond the cancer cell to orchestrate a pro -tumorigenic microenvironment [6][7][8][9][10][11] . Within the tumor microenvironment (TME), immune cells and fibroblasts are amongst the most commomly cell types found 6,12 .…”