Main Session
Sep
28
PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology
Presenter(s)
Michael Spiotto, MD, PhD - MD Anderson Cancer Center Houston, Houston, TX
F. R. Saenz1, B. Dabaja2, S. Y. Wu2, N. Daver3, O. Saifi4, J. Phan2, C. D. Fuller5, S. J. Frank2, and M. T. Spiotto2; 1Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 3The University of Texas MD Anderson Cancer Center, Houston, TX, 4Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, 5Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s): The weak immune responses against chronic viral infections share many similarities to ineffective immune responses against cancer. Since Natural killer (NK) cells can suppress anti-viral T cell responses that enable viral persistence, we hypothesized that NK cells inhibit anti-tumor immune responses induced by radiotherapy and enable cancer cell escape. Materials/Methods: All animal experiments were conducted in accordance with the AAALAC International and institutional IACUC guidelines. We utilized two abscopal models: an AML cell line C1498 expressing an SIYRYYGL (SIY) antigen and a Lewis Lung Carcinoma (LLC) cell line expressing an SIINFEKL (SIIN) antigen. For C1498 model, C57BL/6 mice were injected with 2x106 C1498 cells subcutaneously and, 1x106 cells intravenously 10d later. For LLC model, 1x106 cells were injected into the bilateral flank. Subcutaneous tumors on one flank were irradiated with a single dose of 8 Gy to 20 Gy using the XRAD SmART system. Mice were treated with anti-PDL1 antibody (clone 10F.9G2) and/or anti-NK1.1 antibody (clone PK136) at the start of irradiation and every 3 to 4 days. To inhibit lymphocyte egress from lymph nodes, mice were treated with 25 µg of FTY720 i.p. every 2 days for 14 days. Anti-SIY or anti-SIIN CD8+ T cell responses were assessed using peptide:MHC tetramers in the peripheral blood after irradiation. Kaplan-Meier plot estimated survival, and groups were compared using the log-rank test. Results: In the C1498 model, treatment with anti-PDL1 significantly increased survival of mice after 8 Gy compared to mice treated with 8 Gy or non-irradiated mice (median survival: 64.5 days for anti-PDL1+8 Gy vs. 30 days for 8 Gy vs. 23 days for 0 Gy groups; p<0.001). While depletion of CD8+ T cells reduced survival, depletion of NK cells increased survival of mice treated with anti-PDL1+8 Gy (median survival: undefined; p=0.04). Improved survival required radiotherapy because treatment of mice with anti-PDL1 and/or anti-NK1.1 alone did not improve survival. In LLC tumors, NK cell depletion combined with anti-PDL1+20 Gy eradicated tumors and improved survival (median survival: undefined for anti-PDL1 + anti-NK1.1 vs. 23.5d for anti-NK1.1 vs. 29.5d for anti-PDL1 vs. 27d for isotype control; p<0.01. Depletion of NK cells was associated with increased anti-SIY T cells in mice bearing C1498 tumors and anti-SIIN T cells in mice bearing LLC tumors. Improved survival depended on lymphocyte egress from lymph nodes as mice treated with FTY720 had worse survival compared to control treated mice. Conclusion: Depletion of NK cells enhanced survival of mice treated with radiotherapy and anti-PDL1 indicating that NK cells inhibit radiation induced anti-tumor immune responses in the draining lymph node. Targeting NK cells may facilitate more robust anti-tumor immune responses in patients treated with radiotherapy and checkpoint blockade.