Pulsed radiotherapy to mitigate high tumor burden and generate immune memory

• Published in: Frontiers in immunology 2022-10, Vol.13, p.984318-984318
• Main Authors: Sezen, Duygu, Barsoumian, Hampartsoum B, He, Kewen, Hu, Yun, Wang, Qi, Abana, Chike O, Puebla-Osorio, Nahum, Hsu, Ethan Y, Wasley, Mark, Masrorpour, Fatemeh, Wang, Jing, Cortez, Maria Angelica, Welsh, James W
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; CD8-Positive T-Lymphocytes; immune memory; Immunologic Memory; Immunology; Immunotherapy; lung cancer; Mice; pulsed radiation; radiotherapy; Receptors, Antigen, T-Cell; Tumor Burden
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.984318

Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used with immune-check-point inhibitors in metastatic disease, especially when immunotherapy fails due to tumor immune evasion. We hypothesized that using high-dose stereotactic radiation in cycles (pulses) would increase T-cell priming and repertoire with each pulse and build immune memory in an incremental manner. To prove this hypothesis, we studied the combination of anti-CTLA-4 and Pulsed radiation therapy in our 344SQ non-small cell lung adenocarcinoma murine model. Primary and secondary tumors were bilaterally implanted in 129Sv/Ev mice. In the Pulsed XRT group, both primary and secondary tumors received 12Gyx2 radiation one week apart, and blood was collected seven days afterwards for TCR repertoire analysis. As for the delayed-Pulse group, primary tumors received 12Gyx2, and after a window of two weeks, the secondary tumors received 12Gyx2. Blood was collected seven days after the second cycle of radiation. The immunotherapy backbone for both groups was anti-CTLA-4 antibody to help with priming. Treatment with Pulsed XRT + anti-CTLA-4 led to significantly improved survival and resulted in a delayed tumor growth, where we observed enhanced antitumor efficacy at primary tumor sites beyond XRT + anti-CTLA-4 treatment group. More importantly, Pulsed XRT treatment led to increased CD4 effector memory compared to single-cycle XRT. Pulsed XRT demonstrated superior efficacy to XRT in driving antitumor effects that were largely dependent on CD4 T cells and partially dependent on CD8 T cells. These results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and sustained antitumor response.