Systems approaches to characterize the local heterogeneities in NK cell antitumor immunity in MHC I-disparate human non-small cell lung cancer

Newswise — Checkpoint immunotherapy has shown encouraging yet limited success in non-small cell lung cancer (NSCLC) patients. We combined multiplexed fluorescence imaging with quantitative spatial analysis to investigate antitumoral immunity in NSCLC. As seen before, we observed frequent MHC class I (MHC I) loss and development of CD8 T cell refractory tumors. MHC I-deficiency suggested NK cells may confer protection in NSCLC. Indeed, we found higher CD3^– CD56⁺ NK cell numbers were associated with both disease-free and overall survival. Using partial least squares regression, we found that both T cells and NK cells were significantly enriched in MHC I-bearing tumors. Quantitative spatial characterization of tumor cell MHC I expression revealed vast intra- and inter-tumoral heterogeneity, which was highly associated with the local lymphocyte landscape. To infer functional differences in local cell-cell communication, we built computational models based on spatial single cell neighborhood profiles to discriminate between IFNg-disparate lymphocytes. We found IFNg⁺ NK cells more frequently associated with other IFNg⁺ NK cells or T cells in comparison to IFNg^- NK cells, or IFNg⁺ T cells which more frequently had IFNg^- lymphocyte neighbors. Moreover, IFNg⁺ NK cells were unique in their capacity to also associate with MHC I^– tumor cells. Together these data implicate a key role for NK cells in recruiting and activating other lymphocytes in MHC I-bearing tumors, and further suggest NK cells may be key to developing effective therapies even in CD8 T cell refractory tumors.