Co-expression of receptor tyrosine kinases and CD8 T-lymphocyte genes is associated with distinct prognoses, immune cell infiltration patterns and immunogenicity in cancers.

ABSTRACT

Tumor angiogenesis and the immune microenvironment are 2 essential aspects of the tumor microenvironment (TME). The combination of receptor tyrosine kinase (RTK) inhibitor (TKI)-mediated antiangiogenic therapy and CD8 T-lymphocyte-mediated immunotherapy has become an important focus of cancer treatment, with good results for many tumor types. However, the complex regulatory interactions between these 2 treatment strategies have not been elucidated. Therefore, we systematically investigated the association between the RTKs and CD8 T-lymphocyte genes (CD8Ts) across cancers. We comprehensively evaluated alterations in RTK genes across cancers and examined the co-expression of RTKs and CD8Ts using a weighted gene co-expression network analysis. We found that RTKs exhibited extensive genetic alterations across cancers and were significantly related to the activity of cancer hallmark-related pathways. We identified co-expression between the RTKs and CD8Ts. The low co-expression score subtype was associated with significant better clinical benefits and was characterized by a hot immune microenvironment, including more infiltrating immune cells, higher chemokine expression, and stronger immunogenicity, such as the tumor mutation burden and neoantigens. Two immunotherapy cohorts confirmed that patients with low co-expression scores had an inflamed TME phenotype and significant therapeutic advantages. Then, 4 co-expression patterns were identified, with different patterns reflecting different prognoses and immune microenvironments. The RTKlowCD8Thigh group was associated with the best prognosis and immune-activated microenvironment. In summary, the present study indicates co-expression of RTKs and CD8Ts, which supports the potential application of the combination of inhibiting RTKs activity via TKI-targeted therapy and increasing CD8 T cell activity via immunotherapy in the treatment of cancer.