If clinicians could stop mutations of the KRAS gene—which are present in more than 90% of pancreatic cancer cases and drastically reduce the response to immunotherapy—the chances of improving treatment for the disease would be increased. A collaborative study published by Ischenko et al in Nature Communication has taken an initial step toward better understanding how KRAS drives immune evasion and demonstrated lowering KRAS activity resulted in a more favorable immune environment to fight cancer.
Previous strategies to block the KRAS oncogene therapeutically have focused on counteracting its growth-promoting role in cancer.
“Instead, our study shows that oncogenic KRAS plays a profound immunosuppressive role in cancer maintenance, and that treatment of cancer will be improved by simultaneously inhibiting KRAS and activating immune pathways suppressed by the cancer,” said study author Oleksi Petrenko, PhD, Research Assistant Professor in the Department of Microbiology and Immunology in the Renaissance School of Medicine at Stony Brook University.
Genetic Model
The researchers used a genetic laboratory model of pancreatic ductal adenocarcinoma to demonstrate that at an advanced tumor stage, dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retained the ability to form tumors in immunodeficient mice; however, they failed to evade the immune system in immunocompetent wild-type mice, triggering a strong antitumor response.
The authors also identified BRAF and MYC as key mediators of KRAS-driven tumor immune suppression; the loss of BRAF effectively blocked tumor growth in mice.
“The key insight of the paper’s findings is that mutations in KRAS not only promote tumor growth but also keep tumors ‘cold,’ rather than ‘hot’ when cytotoxic T cells are attacking the cancerous cells,” said study author R. Scott Powers, PhD, Professor in the Department of Pathology in the Renaissance School of Medicine and Director of Clinical Cancer Genomics at the Stony Brook University Cancer Center.
“We believe that this study clearly demonstrates the ability of oncogenic KRAS to corrupt our antitumor immune responses,” added study author Nancy C. Reich, PhD, Professor in the Department of Microbiology and Immunology. “It highlights the need to develop therapeutic interventions that not only target KRAS pathways but that engage immune cell defense.”
Disclosure: The research was supported in by the National Cancer Institute and the Catacosinos Cancer Research Award. For full disclosures of the study authors, visit nature.com.
