MHC-I-Driven Antitumor Immunity Counterbalances Low Absorbed Doses of Radiopharmaceutical Therapy

Preclinical and clinical studies increasingly show that the immune response plays a major role in radiotherapy. Here, we investigated the role of major histocompatibility complex class I (MHC-I) molecules recognized by cytotoxic CD8⁺ T cells in the response to radiopharmaceutical therapy (RPT). Methods: Two murine melanoma cell lines that express low and high MHC-I levels (B16F10 and B16K1, respectively) were grafted in syngeneic or athymic and nude mice, and the response to a single injection of [²²⁵Ac]Ac-DOTA-TA99 monoclonal antibodies (9.25 or 18.5 kBq) was assessed and related to dosimetry. For clinical relevance, MHC-I expression was determined in samples from patients with well-differentiated, iodine-avid metastatic thyroid cancer and well-differentiated grade 2 mid-gut neuroendocrine tumors. Results: RPT efficacy was enhanced by T-cell presence and MHC-I expression. In mice harboring B16F10 and B16K1 melanoma tumors, RPT showed a stronger antitumor effect in C57BL/6J (immunocompetent) animals than in athymic and nude (immunodeficient) animals, suggesting a crucial role of T-cell-mediated immune responses. Moreover, the response to irradiation was the same in B16K1 MHC-I_high tumors with a low absorbed dose of α-RPT and in B16F10 MHC-I_low tumors with a 4 times higher absorbed dose. These results indicate that CD8⁺ T cells can counterbalance low tumor irradiation. Conversely, delivering high absorbed doses leads to side effects and seems to prevent immune system activation, thereby not taking advantage of these mechanisms. Our results also indicate that MHC-I can be used as a predictive biomarker of RPT response in lesions receiving low absorbed doses and that RPT treatment regimens should be reconsidered in the function of the MHC-I expression level. Conclusion: This study shows that MHC-I expression can predict RPT immunostimulatory effects. This is relevant in metastatic disease where lesions in the same patient can receive very low or very high absorbed doses.