Fig. 2

Schematic representation of the negative regulation of anti-tumor immune responses of PD-1/PD-L1 in NSCLC and SCLC. (A) PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated tumor-associated macrophages (TAMs). PD-L1 overexpression on macrophages might be induced via STAT3 activation by cancer cell-derived GM-CSF. The interaction of CD47 on tumor cells and signal‐regulated protein (SIRPα) expressed on the surface of macrophages can protect cells from being “eaten” by macrophages in NSCLC patients. TGF-β secreted from cancer-associated fibroblasts (CAF cells) also reduced the proliferation and activation of CD8⁺ T cells. In addition, PD-L1⁺ lung cancer stem (CSC) cells as well as FoxP3⁺ Treg T cells may modify the metastatic lymph-node immune microenvironment in NSCLC patients. Besides, soluble PD-L1 (sPD-L1) might interrupt PD-1 and Anti-PD-1 mAb whereas interaction of sPD-1/sPD-L1 or sPD-1/PD-L1 may reduce inhibition of sPD-L1 or enhance Anti-PD-1 mAb. The interaction of PD-1/PD-L1 between TCRVγ9Vδ2⁺γδ tumor-infiltrating lymphocytes (TILs) and αβ T cells could restrain the activation of T cells. Intratumoral Vδ1 T cells demonstrated natural killer and CD8⁺ T cell function. (B) The role of PD-L1 in SCLC. In the SCLC-Y subtype, YAP1 not only affects PD-L1, but also upregulates CXCL5 to recruit myeloid-derived suppressor cells (MDSCs). YAP1 and Notch1 are complementary and each suppresses neuroendocrine (NE) differentiation