PD-1 Expression in EMPD: Implication for Immunotherapy
Most tumors display novel antigens that are recognized by the host immune system and thus stimulate cell-mediated and humoral pathways. The immune system naturally provides regulatory immune checkpoints to T cell–mediated immune responses. One of these checkpoints involves the interaction between PD-1 on T cells and its ligand PD-L1 on tumor cells.21 When PD-1 binds to PD-L1 on tumor cells, there is inhibition of T-cell proliferation, a decrease in cytokine production, and induction of T-cell cytolysis.22 The Figure summarizes the dynamics for T-cell regulation.
Naturally, tumor-infiltrating T cells trigger their own inhibition by binding to PD-L1. However, certain tumor cells constitutively upregulate the expression of PD-L1. With that, the tumor cells gain the ability to suppress T cells and avoid T cell–mediated cytotoxicity,23 which is known as the adoptive immune resistance mechanism. There have been several studies in the literature investigating the PD-1 signaling pathway in EMPD as a way to determine if EMPD would be susceptible to immune checkpoint blockade. The success of checkpoint inhibitor immunotherapy generally correlates with increased PD-L1 expression by tumor cells.
One study evaluated the expression of PD-L1 in tumor cells and tumor-infiltrating T cells in 18 cases of EMPD.6 The authors identified that even though tumor cell PD-L1 expression was detected in only 3 (17%) cases, tumor-infiltrating lymphocytes expressed PD-L1 in the majority of the cases analyzed and in all of the cases positive for tumor cell PD-L1.6
Another study evaluated PD-1 and PD-L1 expression in EMPD tumor cells and tumor-associated immune infiltrate.5 They found that PD-1 was expressed heavily by the tumor-associated immune infiltrate in all EMPD cases analyzed. Similar to the previously mentioned study,6 PD-L1 was expressed by tumor cells in a few cases only. Interestingly, they found that the density of CD3 in the tumor-associated immune infiltrate was significantly (P=.049) higher in patients who were alive than in those who died, suggesting the importance of an exuberant T-cell response for survival in EMPD.5
A third study investigated protein expression of the B7 family members as well as PD-1 and PD-L1/2 in 55 EMPD samples. In this study the authors also found that tumor cell PD-L1 was minimal. Interestingly, they also found that tumor cells expressed B7 proteins in the majority of the cases.7
Finally, another study examined activity levels of T cells in EMPD by measuring the number and expression levels of cytotoxic T-cell cytokines.24 The authors first found that EMPD tumors had a significantly higher number of CD8+ tumor-infiltrating lymphocytes compared to peripheral blood (P<.01). These CD8+ tumor-infiltrating lymphocytes also had a significantly higher expression of PD-1 (P<.01). They also found that tumor cells produced an immunosuppressive molecule called indoleamine 2,3-dyoxygenae that functions by suppressing T-cell activity levels. They concluded that in EMPD, tumor-specific T lymphocytes have an exhausted phenotype due to PD-1 activation as well as indoleamine 2,3-dyoxygenase release to the tumor microenvironment.24
These studies highlight that restoring the effector functions of tumor-specific T lymphocytes could be an effective treatment strategy for EMPD. In fact, immunotherapy has been used with success for EMPD in the form of topical immunomodulators such as imiquimod.16,25 More than 40 cases of EMPD treated with imiquimod 5% have been published; of these, only 6 were considered nonresponders,5 which suggests that EMPD may respond to other immunotherapies such as checkpoint inhibitors. It is an exciting time for immunotherapy as more checkpoint inhibitors are being developed. Among the newer agents is cemiplimab, which is a PD-1 inhibitor now US Food and Drug Administration approved for the treatment of locally advanced or metastatic cutaneous squamous cell carcinoma in patients who are not candidates for curative surgery or curative radiation.26 Programmed cell death receptor 1 signaling can serve as a potential target in EMPD, and further studies need to be performed to test the clinical efficacy, especially in unresectable or invasive/metastatic EMPD. As the PD-1 pathway is more studied in EMPD, and as more PD-1 inhibitors get developed, it would be a clinical need to establish clinical studies for PD-1 inhibitors in EMPD.