Elective Nodal Irradiation Attenuates the Combinatorial Efficacy of Stereotactic Radiation Therapy and Immunotherapy. Academic Article uri icon

Overview

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. Clin Cancer Res; 24(20); 5058-71. ©2018 AACR.

authors

  • Marciscano, Ariel E.
  • Ghasemzadeh, Ali
  • Nirschl, Thomas R
  • Theodros, Debebe
  • Kochel, Christina M
  • Francica, Brian J
  • Muroyama, Yuki
  • Anders, Robert A
  • Sharabi, Andrew B
  • Velarde, Esteban
  • Mao, Wendy
  • Chaudhary, Kunal R
  • Chaimowitz, Matthew G
  • Wong, John
  • Selby, Mark J
  • Thudium, Kent B
  • Korman, Alan J
  • Ulmert, David
  • Thorek, Daniel L J
  • DeWeese, Theodore L
  • Drake, Charles G

publication date

  • June 13, 2018

Research

keywords

  • Immunotherapy
  • Lymph Nodes
  • Neoplasms
  • Radiosurgery

Identity

PubMed Central ID

  • PMC6532976

Scopus Document Identifier

  • 85052124132

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-17-0040

PubMed ID

  • 29898992

Additional Document Info

volume

  • 24

issue

  • 20