3067 - Combining High-Dose Radiation with Dual CCR8 and PD-1 Blockade to Overcome Tumor Immune Suppression
Presenter(s)
Y. Hu1, H. B. Barsoumian1, A. Huang1, T. Riad2, D. Robinson1, C. Leuschner1, H. G. Roider3, A. Kremer3, M. Gorjanacz3, and J. W. Welsh1; 1Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 2MD Anderson Cancer Center, Houston, TX, 3Bayer AG, Pharmaceuticals, Berlin, Germany
Purpose/Objective(s): Immunoradiotherapy has shown promise in eliciting systemic antitumor responses, yet overcoming immune suppression within the tumor microenvironment remains a critical challenge. This study explores the therapeutic potential of combining high-dose radiation with immune checkpoint blockade and antibody-mediated depletion of CCR8-positive tumor-resident regulatory T cells (Tregs). We treated C57BL/6 mice bearing bilateral MC38 tumors (model for colon cancer) with a combination of a-PD1 and a-CCR8 antibodies, along with irradiation of one of the tumors. The effects on both irradiated and non-irradiated tumors were assessed by evaluating immune cell infiltration and systemic immune responses.
Materials/Methods: Bilateral MC38 tumors were established in female C57BL/6 mice (N=10 per group). The irradiated tumor received high-dose radiation (12 Gy × 3 fractions) on days 7, 8, and 9, while the contralateral tumor was left untreated. a-CCR8 (100 µg) and a-PD1 (200 µg) were administered intraperitoneally on days 5, 9, 12, 16, 19, and 23. Immune cell populations were analyzed using flow cytometry on dissociated tumors collected on day 21.
Results: Radiation alone effectively controlled the growth of the irradiated tumors, while the combination of a-CCR8 and a-PD1 significantly improved control of the non-irradiated tumors and prolonged survival. a-PD1 alone significantly increased Foxp3+ Tregs and CCR8+ expression within Tregs. Although a-CCR8 monotherapy reduced Treg infiltration in the non-irradiated tumors compared to RT alone, depletion was incomplete. a-CCR8+RT increased proliferating (Ki67+) and activated (4-1BB+) CD4 and CD8 T cells compared to RT alone, while triple therapy (a-CCR8+a-PD1+RT) further enhanced activated CD4 T cells. Both a-CCR8+RT and a-PD1+RT increased NK cell infiltration. Triple therapy specifically reduced the PDL1+Ly6G+CD11b+ neutrophil subset, reshaping the immune landscape.
Conclusion: The combination of high-dose radiation with CCR8 depletion and PD-1 blockade enhanced systemic antitumor responses, improved non-irradiated tumor control, and modulated key immune populations, suggesting its potential for effective colon cancer therapies.