Main Session
Sep
28
PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology
2641 - Single-Dose FLASH vs. Conventional-Dose-Rate Proton Effect on Immune Modulation in Murine Prostate Cancer Models
Presenter(s)
Li Wang, MD, PhD - The University of Texas MD Anderson Cancer Center, Houston, Texas
L. Wang1, H. B. Barsoumian1, U. Titt2, Y. Li2, M. Yang1, X. Wang1, Y. Zhang1, G. Fang1, N. Sahoo1, X. R. Zhu1, J. W. Welsh1, and S. J. Frank3; 1The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 3Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s):
Radiation can suppress or activate immune functions and eventually affect tumor treatment outcomes. Ultra-high dose rate FLASH radiotherapy (RT) shows promise for mitigating normal tissue damage. However, effects of FLASH-proton RT (FLASH-PRT) vs conventional-dose-rate PRT (C-PRT) on immune cells are not well characterized. We hypothesized that FLASH-PRT and C-PRT cause different immune-profile effects detectable in peripheral blood and spleen in a mouse model of prostate cancer (PCa).Materials/Methods:
C57/6J mice were implanted with TRAMP-C2 PCa cells [allograft] and randomized (9-10 per group) 18 days later to receive no treatment (Control [Con]) or FLASH-PRT (250 Gy/s) or C-PRT (0.592 Gy/s) in a single 13-Gy dose to a circular 2-cm field in the prostate. Spleens and blood samples (via cardiac puncture) were collected 3 days after RT, stained with a 10-color immunofluorescence-marker panel, flow cytometry markers were used to characterize lymphoid and myeloid compartments, and immune cells were analyzed by flow cytometry. Percentages of immune cell subtypes in blood or spleen were compared between treatment groups with Student's t tests.Results:
In blood, FLASH-PRT decreased PD1+ helper T cells relative to C-PRT (0.66 times, p=0.021) and possibly vs Con (0.72 times, p=0.052). FLASH-PRT decreased myeloid cells vs Con (0.41 times, p=0.011) and possibly vs C-PRT (0.44 times, p=0.055). In spleens, both FLASH-PRT and C-PRT increased the percentages of certain T lymphocytes (Con vs FLASH-PRT vs C-PRT: Tregs: 1 vs 1.57 [p=0.011] vs 1.23 [p=0.022] times; activated helper T cells: 1 vs 2.02 [p=0.002] vs 1.50 [p<0.001] times; and CD4–CD8– T cells: 1 vs 1.47 [p=0.018] vs 1.50 [p=0.002] times). Notably, FLASH-PRT decreased helper T cells (0.93 times, p=0.026) and PD1+ cytotoxic T cells (0.81 times, p=0.045) relative to control; and C-PRT reduced CD4+CD8+ T cells vs control (0.76 times, p=0.002). No other differences in T subtype distribution were noted. In spleens, NKT cells were higher after FLASH-PRT vs Con (3.85 times, p=0.015), or vs C-PRT (3.22 times, p=0.026); FLASH-PRT and C-PRT both reduced myeloid cells (Con vs FLASH-PRT vs C-PRT: 1:0.55 [p=0.001], :0.58 [p<0.001]).Conclusion:
In this PCa model, unique changes induced by FLASH-PRT (e.g., decreases in PD1+ helper T cells and myeloid cells in blood; decrease in PD1+ cytotoxic T cells and increase in NKT cells in spleens) suggest that different strategies are needed for combining immunotherapy with FLASH-PRT vs C-PRT. Additionally, FLASH-PRT and C-PRT produced similar changes in immune cells in spleens (e.g., increases in Tregs, activated helper T cells, and double-negative T cells; and decrease in myeloid cells). Potential mechanisms, changes in immune cells caused by FLASH-PRT vs C-PRT in PCa tumors, and optimal combinations with immunotherapy need further study.