Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor–induced immune responses
Megan Cole, Panayiotis Anastasiou, Claudia Lee, Xiaofei Yu, Andrea de Castro, Jannes Roelink, Chris Moore, Edurne Mugarza, Martin L. Jones, Karishma Valand, Sareena Rana, Emma Colliver, Mihaela Angelova, Katey S.S. Enfield, Alastair Magness, Asher Mullokandov, Gavin Kelly, Tanja D. de Gruijl, Míriam Molina‐Arcas, Charles Swanton, Julian Downward, Febe van Maldegem
Abstract
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 (T regs ) were also found in frequent contact with effector T cells within this community. Lung adenocarcinoma clinical samples showed similar communities. Depleting T regs led to enhanced tumor control in combination with anti–PD-1 and KRAS-G12C inhibitor. Combining T reg depletion with KRAS inhibition shows therapeutic potential for increasing antitumoral immune responses.