Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

Abstract

Immune checkpoint molecules are promising anticancer targets, among which therapeutic antibodies targeting the PD-1/PD-L1 pathway have been widely applied to cancer treatment in clinical practice and have great potential. However, this treatment is greatly limited by its low response rates in certain cancers, lack of known biomarkers, immune-related toxicity, innate and acquired drug resistance, etc. Overcoming these limitations would significantly expand the anticancer applications of PD-1/PD-L1 blockade and improve the response rate and survival time of cancer patients. In the present review, we first illustrate the biological mechanisms of the PD-1/PD-L1 immune checkpoints and their role in the healthy immune system as well as in the tumor microenvironment (TME). The PD-1/PD-L1 pathway inhibits the anticancer effect of T cells in the TME, which in turn regulates the expression levels of PD-1 and PD-L1 through multiple mechanisms. Several strategies have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including combination therapy with other standard treatments, such as chemotherapy, radiotherapy, targeted therapy, anti-angiogenic therapy, other immunotherapies and even diet control. Downregulation of PD-L1 expression in the TME via pharmacological or gene regulation methods improves the efficacy of anti-PD-1/PD-L1 treatment. Surprisingly, recent preclinical studies have shown that upregulation of PD-L1 in the TME also improves the response and efficacy of immune checkpoint blockade. Immunotherapy is a promising anticancer strategy that provides novel insight into clinical applications. This review aims to guide the development of more effective and less toxic anti-PD-1/PD-L1 immunotherapies.

Keywords: Combination therapy; Immunotherapy; PD-1/PD-L1; PD-L1 regulation.

Fig. 1

PD-1/PD-L1 interaction mediated T cell inhibition. Factors that regulate PD-L1 expression mainly includes (1) genomic aberrations, (2) microRNA-based control, (3) oncogenic transcription factors and pathways and (4) posttranslational regulation and transport. The RAS/MEK/ERK, PI3K/Akt/mTOR, JAK/STATs signaling and TLRs/IKKs pathways are the main pathways regulating PD-L1 expression. IRF1, STATs, MYC, NF-κB, c-Jun and HIF1α/2α are the main downstream transcription factors. Posttranslational modifications of PD-L1 include phosphorylation, ubiquitination, glycosylation and palmitoylation. Induction of PD-L1 by cytokines, such as IFN-γ, is considered a secondary mechanism. Activation of PD-1/PD-L1 signaling leads to the recruitment of the phosphatase SHP-2 to the C-terminal of the ITSM, which downregulates the RAS-MEK-ERK and PI3K-Akt-mTOR pathways and attenuates LCK-induced phosphorylation of ZAP70. In addition, SHP-2 induces the expression of BATF, which inhibits the expression of some effector genes. In general, activation of PD-1/PD-L1 signaling leads to the inhibition of T cell proliferation and activation. Activation of PD-1/PD-L1 can be blocked by anti-PD-1/PD-L1 antibodies. In addition, APCs uptake tumor antigens and regulate T cell responses through the interaction between major MHC and TCRs. APCs (dendritic cells) regulate T cell activity through modulating the interaction between PD-L1/PD-L2 and PD-1 and the interaction between B7 and CD28. CTLA-4 is a negative regulator of costimulation that is activated in the recognition of specific tumor antigens presented by APCs

Fig. 2

Combination strategies to enhance the therapeutic efficacy of PD-1/PD-L1 blockade. A Combination therapy with PD-1 and CTLA-4 blockers. The activation of PD-1/PD-L1 and CTLA-4 can be blocked by anti-PD-1/PD-L1 and CTLA-4 antibodies, respectively. The combined application of PD-1 and CTLA-4 inhibitors produces synergistic effects. B Combination therapy with chemotherapy. Chemotherapy is able to induce ICD, promote the release of tumor antigens and DAMPs, activate DCs, induce local production of CXCL10, recruit T cells to the tumor bed and enhance the differentiation of antitumor-specific CTLs. Chemotherapy can also reduce the number of immunosuppressive cells, such as MDSCs and Tregs. However, systemic chemotherapy shows undifferentiated toxicity to tumor cells and the anticancer immune system, while local chemotherapy enhances immunotherapy by remodeling the TME and attracting activated immune cells to the tumor region. C Combination therapy with radiotherapy. Radiotherapy markedly upregulates the cell adhesion factors ICAM-1 and VCAM-1 on the surface of cancer cells. One of the mechanisms by which radiotherapy may enhance immunotherapy is through activation of certain types of club cells which release proteins that are beneficial to immunotherapy. D Combination therapy with an AMPK activator. Reduced PD-L1 levels in the presence of AMPK activation could enhance the efficacy of combining ICB with an AMPK activator. E Combination therapy with STING agonists. The cGAS-STING pathway is essential for linking the innate immunity and adaptive immunity against cancers. Cancer cells can escape immune surveillance by inactivating the cGAS-STING pathway. Therefore, ICB can be combined with STING agonists to boost the efficacy of immunotherapy. F “Cold” tumors lack activated tumor-specific T cells, which may contribute to primary resistance to ICBs. Effective combination therapy can turn these tumors into hot tumors that are sensitive to ICBs