Combination Radiation Therapy and PARP Inhibition Enhances Responsiveness To Anti-PD-1 Therapy In Colorectal Tumor Models

Abstract

Materials/Methods: The CSF-1R inhibitor BLZ-945 was used to examine the impact of CSF-1R inhibition on M2 polarization using in vitro assays. Then, using an orthotopic, immunocompetent murine GBM-model, mice were treated with vehicle control, RT, BLZ-945, or RT concurrently with BLZ-945. Survival and changes in the immune landscape were compared between treatment arms. Results: BLZ-945 significantly reduced M2 polarization from bone marrow-derived monocytes in vitro. BLZ-945 alone did not result in improvement in median overall survival (mOS Z 29 days) when compared to control mice (mOS Z 27 days). RT led to a significant improvement in survival (mOS Z 45 days; p Z 0.02), while the combination of RT + BLZ-945 led to a further improvement in survival when compared to RT alone (mOS not reached; p Z 0.005) with >70% of mice achieving longterm survival. Correlative studies performed on tumors resected from these mice identified a relatively large population of M2 TAMs in GBM at baseline that was further increased in response to RT. BLZ-945 mitigated the increase in M2 infiltration in response to RT. CD8 T-cells also increased significantly in response to RT. The ratio of M2 to CD8 cells was significantly lower in the BLZ-945 treated mice. Conclusion: Inhibition of CSF-1R with BLZ-945 improved the efficacy of RT in the treatment of GBM in a mouse model and may represent a promising strategy to improve RT-induced antitumor immune responses.

Radiotherapy/Chemotherapy-Immunotherapy for Cancer Management: From Mechanisms to Clinical Implications

“…Radiotherapy was reported to upregulate PD-L1 expression by increasing type I interferon (IFN) in the TME to avoid effector T cells [40,41]. In addition, radiotherapy combined with a programmed cell death protein 1 inhibitor achieved surprisingly encouraging results in colorectal cancer [42], lung cancer [43], Merkel cell carcinoma [44], and other cancers. Nevertheless, some side effects (such as noninfectious inflammation) were also observed [45].…”

The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors

“…It was reported that DDR induced the expression of MHC I and antigen presenting, 74 and PARP inhibition could upregulate MHC I. 75 The PARPi lead to DDR and immunogenic cell death (ICD), thus inducing damage-associated molecular patterns (DAMPs) to promote recruiting APCs. 76 Immune checkpoint inhibitors function to inhibit tumor growth by restoring and enhancing T-cell activation, and T-cell-DC crosstalk involving the cytokines IFN-γ and IL-12 is essential for improved ICI response.…”

Immunotherapy for the treatment of colorectal cancer

“…Other strategies have been investigated in preclinical models to increase responsiveness to ICI through induction of proimmunogenic changes in tumor cells. For example, the combination of PARP inhibition (with veliparib) and subablative doses of ionizing radiation was shown in an in vivo unilateral flank tumor model to synergistically increase surface localization of MHC‐1 and PD‐L1 and to prolong anti‐PD1‐mediated tumor growth delay, an effect dependent onCD8 + T‐cells 102 …”