The Interplay between PARP Inhibitors and Immunotherapy in Ovarian Cancer: The Rationale behind a New Combination Therapy

Abstract

Ovarian cancer (OC) has a high impact on morbidity and mortality in the female population. Survival is modest after platinum progression. Therefore, the search for new therapeutic strategies is of utmost importance. BRCA mutations and HR-deficiency occur in around 50% of OC, leading to increased response and survival after Poly (ADP-ribose) polymerase inhibitors (PARPis) administration. PARPis represent a breakthrough for OC therapy, with three different agents approved. On the contrary, immune checkpoint inhibitors (ICIs), another breakthrough therapy for many solid tumors, led to modest results in OC, without clinical approvals and even withdrawal of clinical trials. Therefore, combinations aiming to overcome resistance mechanisms have become of great interest. Recently, PARPis have been evidenced to modulate tumor microenvironment at the molecular and cellular level, potentially enhancing ICIs responsiveness. This represents the rationale for the combined administration of PARPis and ICIs. Our review ought to summarize the preclinical and translational features that support the contemporary administration of these two drug classes, the clinical trials conducted so far, and future directions with ongoing studies.

Keywords: BRCA; HRD; ICIs; OC; PARP inhibitors; durvalumab; immune checkpoint inhibitors; niraparib; olaparib; ovarian cancer.

Figure 1

The interplay between PARP inhibitors (PARPis) and immune checkpoint inhibitors (ICIs). When double-strand DNA breaks (DSBs) occur and PARPis block PARP complex, DNA fragments accumulate in the cytoplasm. As a result, neo-antigens accumulate on the cell surface, where they are recognized by antigen-presenting cells (APCs), activating the immune response. Moreover, the Stimulator of interferon genes (STING) pathway is activated: DNA fragments are recognized by cytosolic sensor cGMP-AMP synthetase (cGAS), cGAS activates 2′-5′ cyclic GMP-AMP (cGAMP), cGAMP switches on STING, STING modulates transcription factors such as Nuclear factor-kappa B (NF-kB), and Interferon regulatory factor 3 (IRF3), resulting in the transcription of related cytokines (Interferon [IFN], IL-6, tumor necrosis factor-alpha [TNFα]), promoting immune response. IFN increases the expression of Programmed Death-Ligand 1 (PD-L1) on the cell surface. The activation of the sensor system Ataxia-Telangiectasia Mutated (ATM)-ATR Serine/Threonine Kinase (ATR)-Checkpoint kinase 1 (CHEK1) in case of DSBs, and the STAT-IRF pathway, increase PD-L1. Finally, DSBs inactivate glycogen synthase kinase 3-beta (GSK3β), responsible for PD-L1 proteasomal degradation, increasing PD-L1 cellular expression. These modifications result in a more immune responsive TME: increased surface neo-antigens, increased PD-L1 expression, cytokines, and chemotactic factors determine an increase in number and function of APCs, T-cells, NK cells, and decrease in immunosuppressive elements such as myeloid-derived suppressor cells and M2 macrophages.

Figure 2

The interplay between PARP inhibitors (PARPis) and immune checkpoint inhibitors (ICIs): modifications of soluble factors and cell of tumor microenvironment (TME) in ovarian cancer (OC). After the administration of PARPis, a series of modifications occur: an increased production and surface exposure of antigens on tumor cells, increased PD-L1 expression, production of cytokines, and chemotactic factors. Antigen-presenting cells (APCs) are enhanced in their function with major histocompatibility complex (MCH) up-regulation and increased in numbers. A higher number of CD4+ and CD8+ T-cells, and NK cells, are recruited at tumor sites, resulting in higher TILs and immune response activation. On the other hand, immune-suppressive elements such as Myeloid-derived suppressor cells (MDCSs) and Tumor-associated macrophages (TAMs) are reduced, as well as inhibitory receptors (such as T-cell membrane protein 3 [TIM-3], Lymphocyte-activation gene 3 [LAG-3]). These modifications shift the TME toward a higher immune responsivity. Targeting Programmed Death-Ligand 1 (PD-L1), PD1, or Cytotoxic T-lymphocytes Associated Protein 4 (CTLA4), ICIs unleash the anti-tumor immune response, potentiating the immune activation against tumor cells. Therefore, combining these two drug classes could result in a higher anti-tumor immune response in OC.