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Kirsten rat sarcoma virus (KRAS)-G12C inhibition causes remodeling of the lung tumor immune microenvironment and synergistic responses to anti-PD-1 treatment, but only in T cell infiltrated tumors. To investigate mechanisms that restrain combination immunotherapy sensitivity in immune-excluded tumors, we used imaging mass cytometry to explore cellular distribution in an immune-evasive KRAS mutant lung cancer model. Cellular spatial pattern characterization revealed a community where CD4+ and CD8+ T cells and dendritic cells were gathered, suggesting localized T cell activation. KRAS-G12C inhibition led to increased PD-1 expression, proliferation, and cytotoxicity of CD8+ T cells, and CXCL9 expression by dendritic cells, indicating an effector response. However, suppressive regulatory T cells (Tregs) were also found in frequent contact with effector T cells within this community. Lung adenocarcinoma clinical samples showed similar communities. Depleting Tregs led to enhanced tumor control in combination with anti-PD-1 and KRAS-G12C inhibitor. Combining Treg depletion with KRAS inhibition shows therapeutic potential for increasing antitumoral immune responses. [ABSTRACT FROM AUTHOR]

The article presents a study on a therapeutic KRASG12C (glycine 12 to cysteine) inhibitor that drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. It discusses that the in vivo KRASG12C inhibitor increases the T cell infiltration and activation. It also describes the mechanism of the KRASG12C inhibition reverses immunosuppression in several preclinical lung cancer models with varying levels of immunogenicity.

Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive COX2 in cancer cells. Oncogenic KRAS potently induced COX2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX2/PGE2 remodeled the tumor microenvironment by inducing proinflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer. Significance: COX2 signaling via prostaglandin E2 is a major mediator of immune evasion driven by oncogenic KRAS that promotes immunotherapy and KRAS-targeted therapy resistance, suggesting effective combination treatments for KRAS-mutant lung cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)