Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy

Area of Science:

• Oncology
• Immunology
• Radiotherapy

Background:

• Strategies to enhance tumor inflammation are crucial for improving immunotherapy efficacy.
• Immune-cold tumors, characterized by scarce immune cell infiltration, are often resistant to immunotherapy.

Purpose of the Study:

• To investigate the potential of low-dose radiotherapy (LDRT) in sensitizing tumors to immunotherapy.
• To elucidate the immunological mechanisms underlying LDRT's effects on the tumor microenvironment.
• To translate preclinical findings into a clinical setting for patients with immune-desert tumors.

Main Methods:

• Murine tumor models treated with LDRT and combinatorial immunotherapy.
• Flow cytometry and molecular analyses to assess immune cell populations (CD4+, CD8+, dendritic cells) and cytokine profiles (IFN).
• Phase I clinical trial in patients with metastatic immune-cold tumors receiving LDRT, low-dose cyclophosphamide, and immune checkpoint blockade.

Main Results:

• LDRT promoted T-cell infiltration, predominantly CD4+ T cells with exhausted effector and Th1 signatures, in a manner dependent on interferon (IFN).
• LDRT induced activation of dendritic cells expressing NKG2D ligand RAE1, alongside CD4+ and CD8+ T cells expressing NKG2D.
• Clinical trial demonstrated that the combination therapy triggered T-cell infiltration in responsive patients with metastatic immune-cold tumors.

Conclusions:

• LDRT effectively reprograms the tumor microenvironment of immune-cold tumors, enhancing responsiveness to immunotherapy.
• The combination of LDRT and immunotherapy mobilizes both innate and adaptive immunity, particularly CD4+ effector T cells, for tumor control.
• This therapeutic approach shows clinical benefit in patients with metastatic, immune-cold tumors, highlighting the importance of NKG2D-mediated mechanisms.