Low Doses of PARP Inhibitors As A novel Therapeutic Approach to Enhance The Anti‐Cancer Immunotherapy of PD‐1 Immune Checkpoint Blockade
Authors: Ghonim Mohamed A , Tarhuni Abdelmetalab , Luu Hanh , Dean Matthew , Al‐khami Amir , Ochoa Augusto , Boulares Hamid 
Published: June 2021

Background and Objective

Targeting Poly (ADP) Ribose Polymerase (PARP) is one of the newest effective therapeutic strategies against BRCA‐defective cancers with the ultimate goal of achieving maximal PARP inhibition to induce “synthetic lethality”. The therapeutic use of the FDA‐approved PARP inhibitor, Olaparib is limited by its effects against ovarian or breast BRCA‐mutated cancers only. Moreover, it requires a constant administration of high doses with an alarming rise of the associated resistance. We have previously reported the critical roles of PARP in regulating range of host immune responses. We believe that the reliance on high doses of the PARP inhibitors may be masking important aspects of PARP inhibition which may be harnessed for full clinical benefits of being a potential immunotherapeutic target.

Methods

Syngeneic tumor mouse and cell culture models of cancer were used. Mice received low doses of the PARP inhibitor, Olaparib. Some mice received the immune checkpoint blockade, anti‐PD‐1 antibodies alone or in combination with Olaparib. Tumor volumes were measured at time intervals. Mice were euthanized, tumors and tissues were harvested for further processing and analysis.

Results

PARP inhibition using low dose of Olaparib has significantly reduced the tumor volume, tumor associated‐splenomegaly, and the IL‐6/MCP‐1/TNF‐α cytokines production in non BRCA mutant MCA‐38 cell‐based allograft model. However, such effects were not associated with any alterations in the tumor‐infiltrating immune subsets. Interestingly, the anti tumor effects of the low dose of Olaparib was extremely enhanced by combining with the checkpoint inhibitor; anti‐PD‐1 antibodies. In fact, tumors have completely disappeared in some of the mice receiving the combination therapy. We discovered that low doses of Olaparib selectively interferes with the Immunosuppressive function of Myeloid Derived Suppressor Cells (MDSCs) without altering the function of cytotoxic T‐cells or other anti‐tumor infiltrating immune cells. PARP may be regulating the MDSC function in the tumor microenvironment through controlling the inducible NO Synthase (iNOS) and arginase 1 (ARG1) expression.

Conclusion

Our study shows the potential of using low doses of PARP inhibitors as a novel immunotherapeutic approach for controlling progression of colon cancer as well as many others by differentially blocking the MDSC function. This also may support the notion of leveraging the FDA approved PARP inhibitors to enhance the efficacy of many existing and future immunotherapeutic strategies targeting different types of cancers.

Support or Funding Information

This work was supported, by grants, from the American Cancer Society (RSG‐116608), and the NIH (HL072889, P30GM114732, and P30GM106392).

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.