Prospects for combining immune checkpoint blockade with PARP inhibition

Abstract

The immunogenicity of a cancer cell is derived from accumulated somatic mutations. However, on the contrary to increased immunogenicity, anti-cancer immune response tends to be feeble. This impaired anti-cancer immunity could be attributed to multiple factors including loss of immunodominant epitopes, downregulation of major histocompatibility complex, and immunosuppressive microenvironment, as well as aberrant negative co-stimulatory signals. Immune checkpoint inhibitors block negative co-stimulatory signals such as programmed cell death-1 and cytotoxic T-lymphocyte-associated protein 4, ultimately reactivating anti-cancer immunity. Immune checkpoint inhibitors elicit potent anti-cancer effect and have been approved for multiple cancers. Nevertheless, there still are significant potential improvements for the applications of checkpoint inhibitor, especially considering frequent resistance. Recent studies demonstrated that additional PARP inhibition could alleviate resistance and enhance efficacy of immune checkpoint blockade therapy via promoting cross-presentation and modifying immune microenvironment. We proposed that PARP inhibitors could enhance the priming and tumor-killing activities of T cell, boost the whole cancer-immunity cycle, and thereby improve the response to immune checkpoint blockade. In this review, we focused the latest understanding of the effect of PARP inhibitors on anti-cancer immunity and PARP inhibitors combining immune checkpoint blockade therapy. Moreover, we summarized the preclinical and clinical evidence and discussed the feasibility of this combination therapy in future clinical practice.