Figure 4.

Cellular features of immune subtypes in the tumor immune microenvironment of non-small cell lung cancer (NSCLC). The immune-activated subtype is characterized by the highest levels of intratumoral and intrastromal CD4+ T cells, intrastromal CD20+ B cells, and intratumoral CD8+ T cells. CD20+ B cells present tumor antigens for activating CD4+ cells, and CD20+ B cells proliferate and differentiate into plasma cells to generate antibodies for antineoplastic effects with the help of cytokines secreted by CD4+ cells. The CD8+ T cells activated by CD4+ cells tend to kill the cancer cells in the tumor core directly. The highest levels of intratumoral and intrastromal regulatory T cells (Tregs) and neutrophils were observed in the immune-exempted subtype. Tregs produce immunosuppressive molecules which inhibit the activation and function of CD4+ T cells, CD8+ T cells, CD38+ T cells, and M1 macrophages to disrupt immune surveillance and promote tumor progression. Tregs may also recruit neutrophils through the chemokine ligand–chemokine receptor pathway. The immune-defected subtype has the highest levels of intratumoral and intrastromal cancer stem cells (CSC) and intratumoral macrophages. The macrophages in the immune-defected subtype are educated by the CSC to obtain pro-tumorigenic functions like angiogenesis and induce the exhaustion of anti-tumor cells. The immune-exempted and immune-defected subtypes are associated with a more advanced-stage NSCLC than the immune-activated subtype.