Radiation Biology

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SU_39_2390 - Rescuing Lymphopenia and Adverse Tumor Control Outcomes Following Splenic Radiation in Mouse Models That Recapitulate Human Pancreatic Cancer Radiation Therapy Results

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Rescuing Lymphopenia and Adverse Tumor Control Outcomes Following Splenic Radiation in Mouse Models That Recapitulate Human Pancreatic Cancer Radiation Therapy Results
B. P. Venkatesulu1, L. S. K. Mahadevan1, B. K. Kim2, K. L. Sanders1, A. Vassantachart3, P. K. Singh1, and S. Krishnan1; 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Department of Experimental Radiation Oncology,The University of Texas MD Anderson Cancer Center, Houston, TX, 3Loma Linda University Medical School, Loma Linda, CA

Purpose/Objective(s): Clinical studies have reported treatment-related lymphopenia as an independent predictor of survival in pancreatic cancer. The spleen is a reservoir of resident and circulating CD8 T cells and NK T cells which are dominant regulators of tumor immune surveillance. We studied the effect of mouse splenic irradiation on circulating and resident T cell repertoire and its impact on tumor outcomes following radiation. We also evaluated the role of IL-7 and IL-15 in rescuing lymphopenia and augmenting tumor control

Materials/Methods: We performed focal splenic irradiation (control, 1Gy, 2Gy, or 3Gy once a day for 5 days) to assess alterations in T cell population in peripheral blood (PB) weekly and on day 60 in the irradiated spleen via flow cytometry. We also assessed optimal timing and sequencing of IL-7 and IL-15 to assess tumor growth delay.

Results: Splenic irradiation causes a significant dose-dependent drop in CD8+ T lymphocytes in the PB on day 6 with partial recovery, albeit not to baseline levels, by day 60. On day 60, CD4+CD25+foxp3+T regulatory cells increased in the PB. Consistent with the findings in the PB, irradiated spleens also showed a dose-dependent depletion of CD8+T cells and NK T cells (see table 1). In a separate experiment, IL-7 and IL-15 were administered concurrently and sequentially with radiation of 2Gy x 5 to syngeneic Panc-02 tumor-bearing mice. IL-15 sequenced after RT caused the highest regression of tumor growth compared to concurrent IL-15 or concurrent/adjuvant IL-7. We also found that the IL-15 given after radiation reduced the expression of exhaustion markers PD-L1 and TIM-3. Based on the above findings, on-going experiments assess the ability of IL-15 to rescue CD8+ T cells and NK T cells as well as prevent T cell exhaustion following splenic irradiation to reverse the detrimental effects on tumor outcomes.

Conclusion: Splenic irradiation in murine pancreatic cancer models causes depletion of CD8+ T and NK T cells in PB and spleen with a rise in T regulatory cells in circulation. IL-15 administration in pancreatic cancer bearing mice prevents T cell exhaustion and improves tumor outcomes.
Control 1Gy 2Gy 3Gy
CD8+ T cells – day 0 56.02% 55.03% 63.91% 56.19%
CD8+ T cells – day 3 51.93% 32.42% 30.13% 29.12%
CD8+ T cells – day 6 60.09% 29.48% 22.17% 18.38%
CD8+ T cells – day 12 53.67% 35.15% 38.02% 34.54%
CD8+ T cells – day 20 50.81% 36.40% 36.68% 30.82%
CD8+ T cells – day 60 52.09% 37.81% 35.52% 33.55%
CD4+CD25+foxp3+T regs – day 60 3.61% 3.44% 4.87% 4.55%
CD8+ T cells - day 60 spleen 38.9% 35.60% 27.54% 31.23%
NK T cells – day 60 spleen 4.55% 2.21% 1.21% 1.03%
Flow cytometric analysis in peripheral blood and spleen (average of 5 mice)

Author Disclosure: B.P. Venkatesulu: None. L.K. Mahadevan: None. B. Kim: None. K. Sanders: None. S. Krishnan: Research Grant; NIH, DoD, Celgene, Cancer Prevention and Research Institute of Texas. Royalty; Taylor and Francis Group. Vice-chair, GI translational research program; RTOG.

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