STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition inBRCA-associated breast cancer

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors exert their efficacy by inducing synthetic lethal effects, as well as cGAS/STING-mediated immune responses in BRCA- and other homologous recombination repair-deficient cancer cells. Here we investigated whether the immunologic and therapeutic effects of PARP inhibition in BRCA-deficient breast cancer models could be augmented by synthetic cyclic dinucleotide agonists of STING. Combined PARP inhibition and STING agonism induced a greater degree of STING pathway activation and proinflammatory cytokine production compared to monotherapies in BRCA1-deficient human and mouse triplenegative breast cancer cell lines. In a mouse model of BRCA1-deficient TNBC, the combination also induced an improved immune response compared to either monotherapy alone, evidenced by a greater degree of cytotoxic T cell recruitment and activation, and enhanced dendritic cell activation and antigen presentation. Nanostring mRNA analysis indicated that combinatorial effects were the result of augmented interferon signaling and antigen processing, as well as of heightened leukocyte and dendritic cell functions. Finally, the combination markedly improved anti-tumor efficacy in vivo compared to monotherapy treatment, with evidence of complete tumor clearance and prolongation of survival. These results support the development of combined PARP inhibition and STING agonism in BRCA-associated breast cancer.

An In-Depth Review of Niraparib in Ovarian Cancer: Mechanism of Action, Clinical Efficacy and Future Directions

“…Direct STING agonists have been evaluated in the preclinical setting in combination with PARPi. Preliminary in vitro experiments [26,42] of this combination in BRCA-deficient breast cancer models demonstrated that PARP inhibition and STING agonism can augment STING pathway activation and pro-inflammatory cytokine production along with improved leucocyte and dendritic cell function compared to monotherapy. Clinical evaluation of direct STING agonism with PARP inhibition is not yet underway, but this is likely to change very soon.…”

“…To explore this potential synergy in detail, we need to review the cGAS/STING pathway which underscores the immunomodulatory effects of PARP inhibitors [26]. The cGAS-c-GAMP-STING pathway is activated when cytosolic DNA is sensed by cyclic GMP-AMP synthase (cGAS).…”

The PARP Way to Epigenetic Changes

“…Rucaparib, for example, is commonly used as a maintenance therapeutic alongside platinum-based chemotherapy (cite 30830551). A January 2021 study found that olaparib treatment coupled with stimulator of interferon genes (STING) agonism induces more significant STING activation than STING agonism alone [81]. By increasing cytotoxic T cell response, this combined therapy improved anti-tumor effects significantly [81].…”

“…A January 2021 study found that olaparib treatment coupled with stimulator of interferon genes (STING) agonism induces more significant STING activation than STING agonism alone [81]. By increasing cytotoxic T cell response, this combined therapy improved anti-tumor effects significantly [81]. Furthermore, this effect is more significant when also coupled with checkpoint inhibitors that block PD-1 [82].…”

Therapeutic Associations Comprising Anti-PD-1/PD-L1 in Breast Cancer: Clinical Challenges and Perspectives

“…The combination with anti-PDL1 immunotherapy is promising because, as proven in melanoma, cGAMP would activate and recruit CD8 + T cells in the microenvironment, and cGAS seems essential for the success of PD-L1 treatment [ 114 ]. Interestingly, there seems to be immunological synergy between these treatments, and others capable of strongly inducing breaks in DNA, such as PARPi (especially in BRCA-associated BC) [ 115 ].…”