3109 - The Impact of LET and the Tumor Immune Microenvironment on Differential Response of Genetically Engineered Pancreatic Cancer Models to Carbon Ion Radiotherapy
Presenter(s)
H. J. Meyer1,2, M. Moustafa2,3, S. Eskandarian2,3, M. Akbarpour2,3, N. Schuhmacher2,3, A. Gahlawat2,3, U. Titt1, S. Brons4, T. Tessonnier4, A. Mairani3,4, I. Dokic2,3, A. C. Koong5, A. Abdollahi2,3, and R. Mohan1; 1Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, 2Division of Molecular and Translational Radiation Oncology, Department of Radiation Oncology, Heidelberg Faculty of Medicine (MFHD), Heidelberg University Hospital (UKHD) and Heidelberg Ion-Beam Therapy Center (HIT), Heidelberg, Germany, 3Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany, 4Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany, 5Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
Purpose/Objective(s): High precision and enhanced radiobiological effectiveness (RBE) Carbon Ion Radiotherapy (CIRT) may provide a promising tool to eradicate therapy resistant tumors such as pancreatic ductal adenocarcinoma (PDAC). We hypothesized that CIRT induced activation of the adaptive immune response may enhance RBE in vivo as compared to tumor-cell centric survival observation in vitro. We further aimed to examine the impact and potential distinct radiobiological features of the dose-averaged linear energy transfer (LETd) in CIRT-induced tumor immune microenvironment (TIME) modulation.
Materials/Methods: For in vitro radiosensitivity assessment, two clonally derived (2838c3 and 6419c5) C57BL6 syngeneic PDAC genetically engineered mouse model (GEMM) from LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre; YFP, KPCY mice were used. These cell lines were irradiated with photons (320kVp) and carbon ions (low and high LETd) at doses ranging from 1 Gy to 8 Gy. Colony formation assays assessed cell survival. Photon-based survival data were used to predict biologically equivalent doses for carbon ions across multiple radiobiological models and validated experimentally with carbon beams of low and high LETd.
In vivo, KPCY-2838c3 cells were injected subcutaneously into the right hind limb of C57BL/6 mice. Tumors were irradiated at 3 GyRBE, as determined from radiobiological models, for five fractions using either a 6 MV photon beam or a carbon beam at low and high LETd. Thymus, spleen, abdominal lymph nodes, and tumor tissue were collected 48 hours post-radiation and at tumor growth endpoint for immunohistochemical analysis of the immune compartment. Tumor growth data were analyzed to compare in vivo RBE with in vitro models.Results: Preliminary data reveal a significant divergence between in vitro and in vivo RBE for the same cell line. a/ß ratios obtained from LQ model fits were 10.14 and 8.69 for 2838c3 and 6419c5, respectively. In contrast to comparable radiosensitvity of both models for high-LET CIRT in-vitro, an enhanced radiosensitvity was found in immune responsive 2838c3 compared to immune-cold 6419c5 model in syngeneic setting. Ongoing analyses to further elucidate the role of LETd in modulating immune response will accompany these findings and will be discussed at the conference.
Conclusion: This study highlights the critical need for a more comprehensive evaluation of TIME and immune response effects in determining radiation biological effectiveness across the full spectrum of particle LETd. The observed divergences between in vitro and in vivo RBE indicate that predictive models for particle therapies which use in vitro data alone, are not sufficient to capture the complexity of the tumor, its microenvironment, and the complex interactions between radiation and the immune system.