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Review
. 2017 Aug 23:8:561.
doi: 10.3389/fphar.2017.00561. eCollection 2017.

PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome

Hashem O Alsaab  1   2 , Samaresh Sau  1 , Rami Alzhrani  1   2 , Katyayani Tatiparti  1 , Ketki Bhise  1 , Sushil K Kashaw  1   3 , Arun K Iyer  1   4
Affiliations
Review

PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome

Hashem O Alsaab et al. Front Pharmacol. .

Abstract

Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.

Keywords: PD-1/PDL-1 mechanism; atezolizumab; challenges and new approach; combination immune therapy; immune resistance; immunotherapy; nivolumab; tumor stroma role in PD-1/PD-L1.

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Figures

Figure 1
Figure 1
Timeline of discovery of anti-programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) inhibitors used in cancer immunotherapy from ~1900s to February of 2017.
Figure 2
Figure 2
Statistics representative of number of clinical trials for PD-1 and PD-L1 inhibitor with highlight on currently for FDA approved PD-1/PDL-1 inhibitors. All data were obtained from FDA website, Clinicaltrials.gov, and National Cancer Institute.
Figure 3
Figure 3
Mechanism of anti-programmed death 1 (PD-1) receptor and anti-programmed death ligand 1 (PD-L1)/L2 inhibitors mediated cancer immunotherapy. Antigen-presenting cells (APCs) bind to antigen (Ag) that released from tumor cells and T cells to activate T-cell receptor (TCR) and MHC binding. PD-L1 of tumor stroma interacts with PD-1 of T cells to suppress the T-cell mediated tumor cytotoxicity. Tumor associated macrophage (TAM), myeloid derived suppressor cells (MDSC) has crucial role in PD-1/PD-L1 mediated tumor immunosuppression (Ohaegbulam et al., 2015).
Figure 4
Figure 4
(A) Innate immune resistance is driven by activation of PI3K/Akt kinase and IL-6/STAT3 oncogenic signaling that up-modulate PDL-1 protein expression in tumor cells, resulting PD-1/PD-L1 complexation. (B) Adaptive immune resistance of cancer cells is outcome of INF-γ responded PDL1 expression. MHC and TCR interaction helps T-cell activation (Pardoll, 2012).
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References

    1. Agata Y., Kawasaki A., Nishimura H., Ishida Y., Tsubata T., Yagita H., et al. . (1996). Expression of the PD-1 antigen on the surface of stimulated mouse, T and B lymphocytes. Int. Immunol. 8, 765–772. - PubMed
    1. Aguiar P. N., Jr, Santoro I. L., Tadokoro H., de Lima Lopes G., Filardi B. A., Oliveira P. (2016). The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy 8, 479–488. 10.2217/imt-2015-0002 - DOI - PubMed
    1. Alsaab H., Alzhrani R., Kesharwani P., Sau S., Boddu S. H., Iyer A. K. (2017). Folate decorated nanomicelles loaded with a potent curcumin analogue for targeting retinoblastoma. Pharmaceutics 9:15. 10.3390/pharmaceutics9020015 - DOI - PMC - PubMed
    1. Antonia S., Goldberg S. B., Balmanoukian A., Chaft J. E., Sanborn R. E., Gupta A., et al. . (2016). Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1B study. Lancet Oncol. 17, 299–308. 10.1016/S1470-2045(15)00544-6 - DOI - PMC - PubMed
    1. Atkins M. B., Kudchadkar R. R., Sznol M., McDermott D. F., Lotem M., Schachter J., et al. (2014). Phase 2, Multicenter, Safety and Efficacy Study of Pidilizumab in Patients with Metastatic Melanoma. American Society of Clinical Oncology.