Elective nodal irradiation attenuates the combinatorial efficacy of stereotactic radiation therapy and immunotherapy

PURPOSE: In the proper context, radiation therapy (RT) can promote anti-tumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), impacts adaptive immune responses and combinatorial efficacy of RT with immune checkpoint blockade (ICB). EXPERIMENTAL DESIGN: We developed a preclinical model to compare stereotactic RT (Tumor RT) with or without ENI to examine immunological differences between RT techniques that spare or irradiate the DLN. RESULTS: Tumor RT was associated with up-regulation of an intratumoral T-cell chemoattractant chemokine signature (CXCR3, CCR5-related) that resulted in robust infiltration of antigen-specific CD8+ effector T-cells as well as FoxP3+ regulatory T-cells (Tregs). The addition of ENI attenuated chemokine expression, restrained immune infiltration and adversely impacted survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic RT and ICB led to long-term survival in a subset of mice and was associated with favorable CD8 effector-to-Treg ratios and increased intratumoral density of antigen-specific CD8+ T-cells. While RT technique (Tumor RT vs. ENI) impacted initial tumor control and survival, the ability to reject tumor upon re-challenge was partially dependent upon the mechanism of action of ICB; as RT/anti-CTLA4 was superior to RT/anti-PD-1. CONCLUSIONS: Our results highlight that irradiation of the DLN restrains adaptive immune responses through altered chemokine expression and CD8+ T-cell trafficking. These data have implications for combining RT and ICB, long-term survival and induction of immunological memory. Clinically, the immunomodulatory effect of the RT strategy should be considered when combining stereotactic RT with immunotherapy.

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