The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients

Abstract

The programmed death-1 (PD-1), a coinhibitory receptor expressed on activated T cells and B cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. The cancer patients harboring PD-1 or PD ligand 1 (PD-L1) protein expression have often a poor prognosis and clinical outcome. Currently, targeting PD-1 pathway as a potential new anticancer strategy is attracting more and more attention in cancer treatment. Several monoclonal antibodies against PD-1 or PD-L1 have been reported to enhance anticancer immune responses and induce tumor cell death. Nonetheless, the precise molecular mechanisms by which PD-1 affects various cancers remain elusive. Moreover, this therapy is not effective for all the cancer patients and only a fraction of patients respond to the antibodies targeting PD-1 or PD-L1, indicating these antibodies may only works in a subset of certain cancers. Thus, understanding the novel function of PD-1 and genetic determinants of response to anti-PD-1 therapy will allow us to develop a more effective and individualized immunotherapeutic strategy for cancer.

Keywords: PD-1; PD-L1; cancer; checkpoint inhibitor; immunotherapy.

Figure 1. The role of PD-1/PD-L1 pathway in cell immune response

PD-1 functions to inhibit T cell activation not only by attenuating TCR signaling (SHP-1/2), but also by enhancing the expression of genes that impair T cell function. PI3K-Akt-mTOR, JNK, and Ras-MEK-ERK signals are crucial regulators for PD-1-mediated inhibitory effect on T cell immune. PD-L2 is mainly expressed on B cells. Oct2 can regulate PD-L2 gene expression in B-1 cells and at low antigen concentrations, PD-L2-PD-1interactions suppressed B cell function by inhibiting TCR-B7-CD28 signals.