A DNA Repair Inhibitor Targeting ATR Modulates Immune Responses to Radiotherapy
S Bright1*, B Turner2, M Manandhar3, C McFadden4, D Flint5, D Martinus6, M Ben Kacem7, S Shaitelman8, G Sawakuchi9, (1) UT MD Anderson Cancer Center, Houston, TX, (2) UT MD Anderson Cancer Center, Houston, TX, (3) UT MD Anderson Cancer Center, Houston, TX, (4) UT Southwestern, Dallas, TX, (5) UT MD Anderson Cancer Center, Houston, TX, (6) UT MD Anderson Cancer Center, Houston, TX, (7) MD Anderson Cancer Center, Houston, TX, (8) MD Anderson Cancer Center, Houston, TX, (9) UT MD Anderson Cancer Center, Houston, TX
Presentations
TU-C-TRACK 6-1 (Tuesday, 7/27/2021) 1:00 PM - 2:00 PM [Eastern Time (GMT-4)]
Purpose: Radiotherapy (RT) has been shown to induce antitumor immune responses whereby the host immune system is stimulated to recognize tumor and activate mechanisms to clear it. RT-induced antitumor immunity is rare but once achieved it offers robust and long-lasting antitumor immunity. Because RT-induced antitumor immunity is thought to be mediated through DNA damage we set out to establish if inhibitors of DNA damage repair proteins, particularly targeting ataxia telangiectasia and Rad3-related protein (ATR), can induce greater immune responses than RT alone.
Methods: We used a triple negative breast cancer murine model, 4T1, on the hind leg of BALB/c mice. Animals were treated with vehicle or an ATR inhibitor (ATRi) (75 mg/kg, AZD6738) 2 h prior to each radiation fraction (3x6 Gy using 6 MV x-rays) or sham exposure. Tumors were harvested 7 days after the last fraction to isolate sub-populations of immune cells (CD8⁺ T-cells, CD4⁺ T-cells, T-regs, CD8⁺ PD-1⁺ T-cells, type 1 and 2 macrophages and classical dendritic cells type 1 and 2) within the tumor. Tumor growth delay and survival data were also acquired.
Results: RT delayed tumor growth and modestly increased survival. RT+ATRi enhanced these effects significantly. RT alone was able to increase the percentage of macrophages present in the tumor (12.9%) compared to vehicle alone (4.6%). RT+ATRi also increased macrophage numbers (24.8%) but also significantly increased CD4⁺ (9.3% vs vehicle 3.2%) and CD8⁺ (5.6 % vs vehicle 2.6%) T-cells. Dendritic cells were also increased after RT+ATRi.
Conclusion: RT alone can alter the tumor microenvironment by increasing macrophage recruitment. This effect can be increased with RT+ATRi. Furthermore, RT+ATRi significantly increased the number T-cells (CD4⁺ and CD8⁺) and non-significantly, dendritic cells. This suggests differential signaling at 7 days between RT and RT+ATRi. Further analysis is required to identify pro- and anti-tumor subpopulations within these sub-types.
Funding Support, Disclosures, and Conflict of Interest: This research was supported in part by RP170040, 1R21CA252411-01, Emerson Collective, and MD Anderson Cancer Center. Dr. Sawakuchi has research agreements with Alpha Tau Medical and Artios Pharma. Dr. Shaitelman has a research agreement with Exact Sciences.
Handouts
Keywords
Not Applicable / None Entered.
Taxonomy
TH- Radiobiology(RBio)/Biology(Bio): Bio- tissue and microenvironment
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