PV QA 1 - Poster Viewing Q&A 1
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.
|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%|
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