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Abstract
Purpose: 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).Experimental Design: 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.Results: 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.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 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.

Translational Relevance: Mechanistically, ENI modulated chemokine signaling, leading to reduced immune infiltration as well as to an unfavorable balance between tumoricidal and immunosuppressive intratumoral immune cells (reflected in a decreased CD8 effector-to-Treg ratio). Exclusion of the DLN from the radiotherapy target volume should be examined in future clinical trials to promote synergy between ICB and radiotherapy. 

Author information

Marciscano AE1, Ghasemzadeh A2, Nirschl TR2, Theodros D2, Kochel CM2, Francica BJ2, Muroyama Y2, Anders RA2,3, Sharabi AB4, Velarde E1, Mao W2, Chaudhary KR5, Chaimowitz MG6, Wong J1, Selby MJ7, Thudium KB7, Korman AJ7, Ulmert D8, Thorek DLJ2,9, DeWeese TL1,2, Drake CG10,6.
1
Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Radiation Medicine and Applied Sciences, University of California, San Diego, Moores Cancer Center, San Diego, California.
5
Department of Radiation Oncology, Columbia University Medical Center, New York, New York.
6
Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
7
Bristol-Myers Squibb Company, Redwood City, California.
8
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
10
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. cgd2139@cumc.columbia.edu.