Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39485838.
- Also identified by DOI 10.1126/sciadv.adl6464 and PMC identifier 11529713.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup> T cells, and CXCL9 expression by dendritic cells, indicating an effector response. However, suppressive regulatory T cells (T<sub>regs</sub>) were also found in frequent contact with effector T cells within this community. Lung adenocarcinoma clinical samples showed similar communities. Depleting T<sub>regs</sub> led to enhanced tumor control in combination with anti-PD-1 and KRAS-G12C inhibitor. Combining T<sub>reg</sub> depletion with KRAS inhibition shows therapeutic potential for increasing antitumoral immune responses.
Medical subject headings
- T-Lymphocytes, Regulatory
- Lung Neoplasms
- Proto-Oncogene Proteins p21(ras)
- Tumor Microenvironment