Hypofractionated radiotherapy combined with lenalidomide improves systemic antitumor activity in mouse solid tumor...

Area of Science:

• Immunology
• Oncology
• Radiotherapy

Background:

• Hypofractionated radiotherapy (hRT) can induce a T cell-mediated abscopal effect, but it is rare and often combined with toxic immune checkpoint blockade (ICB).
• Lenalidomide (lena), an immunomodulatory drug, has potential to enhance anti-tumor responses.
• This study investigates if lenalidomide can augment the abscopal effect of hRT in solid tumor models.

Purpose of the Study:

• To evaluate the efficacy of a combination therapy of lenalidomide and hRT in solid tumor models.
• To elucidate the underlying immunological mechanisms, including the role of CD8+ T cells, type-I IFN signaling, and dendritic cell (DC) cross-presentation.

Main Methods:

• Syngeneic bilateral tumor models (B16-CD133 melanoma, MC38 colon carcinoma) were used.
• Primary tumors received hRT, while lenalidomide was administered daily.
• Antitumor effects were assessed by tumor size and survival, with mechanistic studies involving CD8+ T cell quantification, differentiation analysis, DC cross-presentation assays, and gene expression profiling.

Main Results:

• The hRT/lena combination significantly induced an abscopal effect in both tumor models, improving tumor control and survival compared to monotherapies.
• The abscopal effect was CD8+ T cell-dependent, associated with increased tumor-specific CD8+ T cells with stem-like and exhausted phenotypes, and enhanced DC cross-presentation.
• Lenalidomide boosted type-I IFN signaling in DCs, promoting maturation and costimulatory molecule expression (CD70, CD83, CD86), which was crucial for the abscopal response.

Conclusions:

• Lenalidomide enhances the hRT-induced abscopal effect in mouse solid tumors via CD8+ T cell and type-I IFN-dependent mechanisms.
• The combination therapy promotes anti-tumor CD8+ T cell immunity, DC cross-presentation, and increases tumor-associated high endothelial cells (TA-HECs).
• These findings support the potential clinical application of lenalidomide and hRT combination for (oligo)metastatic patients.