PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1/PD-L1 Blockade Immunotherapy

Abstract

The use of monoclonal antibodies targeting PD-1/PD-L1 axis completely changed anticancer treatment strategies. However, despite the significant improvement in overall survival and progression-free survival of patients undergoing these immunotherapy treatments, the only clinically accepted biomarker with some prediction capabilities for the outcome of the treatment is PD-L1 expression in tumor biopsies. Nevertheless, even when having PD-L1-positive tumors, numerous patients do not respond to these treatments. Considering the high cost of these therapies and the risk of immune-related adverse events during therapy, it is necessary to identify additional biomarkers that would facilitate stratifying patients in potential responders and non-responders before the start of immunotherapies. Here, we review the utility of PD-L1 expression not only in tumor cells but in immune system cells and their influence on the antitumor activity of immune cell subsets.

Keywords: PD-L1; biomarkers; checkpoint inhibition; immune; immunotherapy; liquid biopsy; systemic myeloid subsets.

Figure 1

While clinical responses of cancer patients undergoing PD-1/PD-L1 blockade therapies may be explained by the suppression of the canonical PD-L1/PD-1 signaling axis, the fact that some patients with negative tumor PD-L1 expression still achieve objective responses highlights the contribution of PD-L1⁺ systemic immunity—particularly the myeloid compartment—to this kind of treatment. sPD-L1, soluble PD-L1; MDSC, myeloid derived suppressor cells; CTC, circulating tumor cell; DC, dendritic cell; APC, antigen presenting cell.