Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model
Yonghong Liu, Jincheng Han, Wen‐Hao Hsu, Kyle A. LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallón de Lara, Li Cai, Shan Jiang, Ronald A. DePinho
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy (IO). In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. In this study, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust antitumor regression in iKPC mice bearing large autochthonous tumors. Whereas untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T-cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside IO as a potential PDAC treatment avenue, warranting clinical investigation. Significance: Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.