Abstract
PARP inhibitors (PARPi) have shown promising clinical results and have revolutionized the landscape of ovarian cancer management in the last few years. While the core mechanism of action of these drugs has been largely analyzed, the interaction between PARP inhibitors and the microenvironment has been scarcely researched so far. Recent data shows a variety of mechanism through which PARPi might influence the tumor microenvironment and especially the immune system response, that might even partly be the reason behind PARPi efficacy. One of many pathways that are affected is the cGAS-cGAMP-STING; the upregulation of STING (stimulator of interferon genes), produces more Interferon ϒ and pro inflammatory cytokines, thus increasing intratumoral CD4+ and CD8+ T cells. Upregulation of immune checkpoints such as PD1-PDL1 has also been observed. Another interesting mechanism of interaction between PARPi and microenvironment is the ability of PARPi to kill hypoxic cells, as these cells show an intrinsic reduction in the expression and function of the proteins involved in HR. This process has been defined “contextual synthetic lethality”. Despite ovarian cancer having always been considered a poor responder to immune therapy, data is now shedding a new light on the matter. First, OC is much more heterogenous than previously thought, therefore it is fundamental to select predictive biomarkers for target therapies. While single agent therapies have not yielded significant results on the long term, influencing the immune system and the tumor microenvironment via the concomitant use of PARPi and other target therapies might be a more successful approach.
Highlights
AND STATE OF THE ARTOver the past decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have completely revolutionized the landscape of Ovarian Cancer (OC) treatment
While the association between chemotherapy and PARPi has been proven to be burdened by greater toxicities, there are currently a number of trials focusing on PARPi in other scenarios; in the single agent setting [ARIEL4 for Rucaparib [5] and SOLO3 for Olaparib [6]], and in association with other target therapies such as Cediranib, an anti VEGFR [ICON9 [7]] or ICI such as Nivolumab (ATHENA) [8]
While CD4+ T cells were incremented, the Treg phenotype was not found to be more expressed, suggesting a higher T helper differentiation. mRNA levels of INFb, CCL5, and CXCL10, potent proinflammatory signals that correlate to T cell infiltration, were found to be overexpressed. This was not the case in a BRCA1 proficient setting. These findings suggest that PARPi is a potent inductor of both cytotoxic cells recruitment and activation, but the effect is a lot more prominent in a homologous repair deficiency (HRD) deficient or BRCA mutated models [44, 45]
Summary
AND STATE OF THE ARTOver the past decade, poly(ADP-ribose) polymerase inhibitors (PARPi) have completely revolutionized the landscape of Ovarian Cancer (OC) treatment. Far PARPi have been considered effective in BRCA mutated and HRD defective cells; the new concept of contextual synthetic lethality, whereby external conditions such as hypoxia can alter the tumor cell mechanisms rendering them susceptible to target therapies, is surely worth exploring further and can offer new scenarios for clinical setting that were previously thought to be immune to PARPi [38].
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