Figure 3.

Schematic diagram of the difference in the mechanism of CIP mediated by PD-L1 inhibitor and PD-1 inhibitor monotherapy. The mechanisms of checkpoint inhibitor pneumonitis (CIP) induced by PD-1 inhibitors and PD-L1 inhibitors in patients with NSCLC are not completely the same and may be related to PD-1 ligands, including PD-L1 and PD-L2. PD-L1 blockade does not influence the binding between PD-L2 and its receptor PD-1, which is associated with immune tolerance in lung tissue. PD-1 inhibitors can simultaneously block the interaction between PD-1 and its ligands, including PD-L1 and PD-L2. The blockade of PD-1-PD-L2 signaling by PD-1 inhibitors has been observed to increase cytokine production and/or CD4+ T cell proliferation, which can increase the incidence and severity of CIP compared with PD-L1 inhibitors. Moreover, the application of a PD-1 inhibitor can increase the binding of PD-L2 to repulsive guidance molecule b (RGMb). RGMb has been observed to be expressed in lung interstitial macrophages, alveolar epithelial cells and other cells of the immune system. The interaction of RGMb–PD-L2 can increase T cell activity to self-antigens by increasing the clonal expansion of T cells that reside in the lung and then damage normal lung tissue. NSCLC, non-small cell cancer; CIP, checkpoint inhibitor pneumonitis; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand-1; PD-L2, programmed cell death protein ligand-2; RGMb, repulsive guidance molecule b.