Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy

Abstract

In the proper context, radiotherapy can promote antitumor immunity. It is unknown if elective nodal irradiation (ENI), a strategy that irradiates tumor-associated draining lymph nodes (DLN), affects adaptive immune responses and combinatorial efficacy of radiotherapy with immune checkpoint blockade (ICB). We developed a preclinical model to compare stereotactic radiotherapy (Tumor RT) with or without ENI to examine immunologic differences between radiotherapy techniques that spare or irradiate the DLN. Tumor RT was associated with upregulation 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 affected survival when combined with ICB, especially with anti-CLTA4 therapy. The combination of stereotactic radiotherapy 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. Although radiotherapy technique (Tumor RT vs. ENI) affected initial tumor control and survival, the ability to reject tumor upon rechallenge was partially dependent upon the mechanism of action of ICB; as radiotherapy/anti-CTLA4 was superior to radiotherapy/anti-PD-1. 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 radiotherapy and ICB, long-term survival, and induction of immunologic memory. Clinically, the immunomodulatory effect of the radiotherapy strategy should be considered when combining stereotactic radiotherapy with immunotherapy. .

Local Irradiation Sensitized Tumors to Adoptive T Cell Therapy via Enhancing the Cross-Priming, Homing, and Cytotoxicity of Antigen-Specific CD8 T Cells

“…Increasing evidence from several studies emphasized the importance of TILs to the effects of cancer treatment in different tumor models (28)(29)(30). In this study, we found that tumor irradiation significantly enhanced the proliferation of antigenspecific T-lymphocytes in vitro.…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…Accidental irradiation of draining lymph nodes is a related consideration. A murine study using MC38 and B16 cell line xenograft models has recently implied that draining-lymph-node irradiation inhibits the induction of CD8 T-cell mediated immunity when checkpoint inhibition and radiotherapy are combined [148]. This is corroborated by the observation, that intratumoral T-cells of murine tumors withstand radiation much more effectively than T-cells in healthy tissue [71].…”

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

“…Translational work from that trial, as for SARC028, is likely to advance our understanding of responses to PD-1 checkpoint blockade plus radiotherapy in sarcoma. Preclinical data have shown the possible deleterious effects of radiotherapy on non-tumour lymphoid tissue 50,51 . With the identification of TLS in sarcoma and the link to responsiveness to pembrolizumab 12 , clinical data on the role of these TLS in radiotherapy plus ICI trials would be highly informative.…”