AI Summary
The research examined the impact of natural killer (NK) cells and CD8 T cells in non-small cell lung cancer (NSCLC) despite the loss of major histocompatibility complex class I (MHC-I) in tumor cells. The study found that NK cells and CD8 T cells can provide a survival benefit even in cases of profound MHC-I loss. High numbers of CD56+ cells in tumors were associated with better disease-free and overall survival. Analysis also revealed that NK and CD8 T cells were enriched in MHC-I-bearing tumors and were more frequently associated with other activated lymphocytes in the tumor microenvironment. The findings suggest that the combined presence of NK and CD8 T cells, especially in the presence of interferon (IFN), plays a significant role in controlling NSCLC tumor progression, highlighting the importance of understanding immune cell interactions in cancer.
Background
Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression.
Methods
We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFN-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis.
Results
Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1x10–3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3–CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell–cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFN+/– NK cells and T cells. We discovered that both IFN+ NK and CD8 T cells were more frequently associated with other IFN+ lymphocytes in comparison to IFN– NK cells and CD8 T cells (p<1x10–30). Moreover, IFN+ lymphocytes were most often found clustered near MHC-I+ tumor cells.
Conclusions
Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFN. Frequent colocalization of IFN+ NK cells with other IFN+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.