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

Area of Science:

• Immunology
• Radiotherapy
• Oncology

Background:

• The immune system significantly influences radiotherapy outcomes.
• Cytotoxic CD8+ T cells recognize major histocompatibility complex class I (MHC-I) molecules.
• The role of MHC-I in radiopharmaceutical therapy (RPT) response remains to be fully elucidated.

Purpose of the Study:

• To investigate the role of MHC-I in the response to RPT.
• To assess the impact of T-cell mediated immunity on RPT efficacy.
• To explore MHC-I as a predictive biomarker for RPT response.

Main Methods:

• Murine melanoma models with low (B16F10) and high (B16K1) MHC-I expression were used.
• Tumors were grafted in immunocompetent and immunodeficient mice, followed by [225Ac]Ac-DOTA-TA99 RPT.
• MHC-I expression was analyzed in patient samples from metastatic thyroid and neuroendocrine tumors.

Main Results:

• RPT efficacy was enhanced by T-cell presence and higher MHC-I expression.
• Immunocompetent mice showed stronger antitumor effects compared to immunodeficient mice.
• High MHC-I tumors with low absorbed doses responded similarly to low MHC-I tumors with higher doses, indicating CD8+ T cells can compensate for lower irradiation.

Conclusions:

• MHC-I expression is a predictive biomarker for RPT immunostimulatory effects.
• MHC-I levels can guide RPT treatment strategies, especially in metastatic disease with variable absorbed doses.
• Optimizing RPT regimens based on MHC-I expression may improve therapeutic outcomes.