Targeting the Dendritic Cell-Secreted Immunoregulatory Cytokine CCL22 Alleviates Radioresistance

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2024 May 1

PMID 38691100

Authors

Jason Bugno

Liangliang Wang

Xianbin Yu

Xuezhi Cao

Jiaai Wang

Xiaona Huang

Kaiting Yang

Andras Piffko

Katherine Chen

Stephen Y Luo

Emile Naccasha

Yuzhu Hou

Sherry Fu

Chuan He

Yang-Xin Fu

Hua L Liang

Ralph R Weichselbaum

Affiliations

Soon will be listed here.

Abstract

Purpose: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that conventional dendritic cells (cDC) maintain Treg, we sought to identify and target cDC signaling to block Treg infiltration after radiation.

Experimental Design: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT but also associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT.

Results: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration.

Conclusions: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy. See related commentary by Kalinski et al., p. 4260.

Citing Articles

Dendritic Cell Plasticity, Radiation, and Newton's Third Law.

Kalinski P, Gandhi S, Kokolus K Clin Cancer Res. 2024; 30(19):4260-4262.

PMID: 39087954 PMC: 11446472. DOI: 10.1158/1078-0432.CCR-24-1506.

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