Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses
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Megan Cole Panos Anastasiou Claudia Lee Xiaofei Yu Andrea De Castro Jannes Roelink Christopher Moore Edurne Mugarza Martin Jones Karishma Valand Sareena Rana Emma Colliver Mihaela Angelova Katey Enfield Alastair Magness Asher Mullokandov Gavin Kelly Tanja D de Gruijl Miriam Molina Arcas Charles Swanton Julian Downward Febe VanMaldegemAbstract
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.
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Journal
Science advances
Volume
10
Issue number
44
Pages
eadl6464
Available online
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10.1126/sciadv.adl6464
Europe PubMed Central
39485838
Pubmed
39485838
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