Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape

Abstract

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

Keywords: Inflammatory factor; PD-1; PD-L1; Tumor immune escape; Tumor microenvironment.

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The authors declare that they have no competing interests.

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Figures

Fig. 1

Cell growth factors and cytokines secreted in the tumor microenvironment. Abbreviations: CAFS, cancer-associated fibroblasts; Mφ, macrophage; Breg: B regulatory cell; T cells, T lymphocytes; NK, natural killer cell; DC, dendritic cells; TAN, tumor-associated neutrophil; MDSC, myeloid-derived suppressor cell; TAAC, tumor-associated adipose cells; VEC, vascular endothelial cell; ECM, extracellular matrix

Fig. 2

PD-1 signaling in B cells and T cells. a In B cells, upon PD-1 activation, SHP-2 is recruited to the C-terminal of PD-1 and dephosphorylates downstream members of the BCR pathway (e.g., SyK, Igα/β), thereby disrupting the normal BCR response as well as inhibiting PLCγ2, ERK, and PI3K signaling. This PD-1 activation consequently reduces the stability of the immunological synapse as well as B cell cycle arrest and causes disorder of Ca2+ mobilization. b In T cells, when PD-1 combines with PD-L1, SHP-1/2 are recruited to the C-terminal of PD-1 immediately and dephosphorylate key signal transducers, including the ZAP70, CD3δ, and PI3K pathways, thus suppressing TCR-mediated cell proliferation and cytokine production

Fig. 3

The regulation network of PD-1 in the tumor microenvironment

Fig. 4

Epigenetic modification of PD-L1 by the tumor microenvironment. a IFN-γ can regulate the translation of PD-L1 mRNA via upregulating miR-155 or downregulating miR-513, and EGF can enhance the mRNA stability via the RAS-ERK1/2-TPP pathway. b EGF can reduce PD-L1 degradation via upregulating B3NT3 or downregulating GSK3β; alternatively, EGF can enhance PD-L1 protein stability via the PTEN/PI3K/mTOR /S6K1 pathway

Fig. 5

Transcription regulation network of PD-L1 in the tumor microenvironment

Fig. 6

Role of non-coding RNAs in regulating PD-L1