PD-1 Immune Checkpoint Inhibitor Therapy Malignant Tumor Based on Monotherapy and Combined Treatment Research

Abstract

Recently, immunotherapy has become the fourth pillar of cancer treatment in addition to surgery therapy, chemotherapy, and radiation therapy. The inhibitors of programed cell death protein 1 (PD-1) and its ligand PD-L1 are the new stars in immunotherapy, as they can overcome tumor immunosuppression. However, the efficacy of PD-1 inhibitors still needs to be further developed for clinical treatment. Therefore, research into treatment with anti-PD-1 drugs has emerged as a new development field. This review provides novel insights into the role and mechanism of PD-1 combination anti-tumor therapy, thereby promoting its clinical application in anti-tumor immunotherapy.

Keywords: PD-1; PD-L1; anti-tumor; immunotherapy; mechanism.

Figure 1.

PD-1/PD-L1 signaling pathway. When PD-1 binds to PD-L1 that is expressed on the surface of tumor cells, it induced PD-1 phosphorylation of the intracellular N-terminal ITIM, thereby recruiting SH2 domain-containing protein tryrosine phosphatase-2 (SHP-2) to C-terminal ITSM tyrosine. The TCR of T cells binds to the MHC presented by APC to complete antigen recognition and can secrete antibodies to tumor cells. The above procedure can be reversed by PD-1 inhibitors (Nivolumab, Pembrolizumab and Atezolizumab). In addition, CD28 and ligands (CD80 and CD86) are exposed to the tumor microenvironment, T cells become unreactive or eliminated by programed cell death.

Figure 2.

Anti-PD-1 combined with other cells inhibiting tumor growth and metastasis. The addition of anti-PD1 to TILs increased RANKL expression, and anti-RANKL directly reduced PD-L1 expression on the non-lymphoid component tumor microenvironment. Therefore, the addition of RANKL blocker can improve the efficacy of PD1, CTLA4 and RANKL inhibitors, and increase the proportion of IFNγ and TNFα in tumor-infiltrating CD4⁺ and CD8⁺ T cells. In addition, CD28 on T cells binds to ligands on DC cells to regulate tumor cells. T cells were activation of co-stimulatory molecules by 4-1BB and 4-1BBL enhances the survival of primary T cell responses and memory T cells. Besides, anti-PD-1 significantly inhibits tumor growth by activating DCs to present tumor-associated antigens to primary T cells. When CIK is activated by binding of the antigen-antibody complex to the FcR, toxic particles are excreted to the cells, and binding of FasL and Fas, the tumor cells undergo apoptosis. In addition to the release of toxic particles and Fas/FasL, CD16 expressed on the surface of NK cells binds to antibodies and kills tumor cells.