Comprehensive comparison of immune features between ultra-low and ultra-high mutation burden non-small cell lung cancers

Abstract Background: Tumor mutation burden (TMB) is associated with the formation of tumors and the outcomes of immunotherapy, especially in non-small cell lung cancers (NSCLC). The aim of this study was to study immune features of NSCLC with different mutation burdens. We performed a comprehensive comparison of immune features, including driver mutations, up- or down-regulated expression of key biological pathways, tumor cell evolution, tumor cell stemness, etiology, and immune cell infiltration, between ultra-low (UL) and ultra-high (UH) TMB NSCLC. Results: Generally, we found that UL-TMB tumors contained a higher proportion of driver mutations and maintained an “immune-desert” tumor microenvironment with reduced effector cell infiltration and increased suppressor cell infiltration. In UH-TMB tumors, the expression levels of cell cycles, DNA replication and mismatch repair pathways were up-regulated. We discovered that UL-TMB tumors had different up-regulated pathways between a denocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Basically, the expression levels of primary bile acid biosynthesis, arachidonic acid metabolism, and drug metabolism pathways were up-regulated in LUAD; however, the expression level of CaM pathway and the PLC-gamma1 signaling pathway were up-regulated in LUSC. Most mutations in UH-TMB tumors occurred in the early stages, while UL-TMB tumors showed the opposite trend. UH-TMB tumors had a relatively high stemness score. Despite the mutations and neo-antigens increasing in UH-TMB tumors, the overall antigen presentation capacity was weak. Conclusions: These results support rational design of therapeutic strategies for NSCLC with different mutation burdens.