Interleukin-4 receptor inhibition targeting metastasis independent of macrophages

Megan M. Cleary, Narendra Bharathy, Jinu Abraham, Jin Ah Kim, Erin R. Rudzinski, Joel E. Michalek, Charles Keller

Research output: Contribution to journalArticlepeer-review

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma occurring in children and carries a dismal prognosis when metastatic disease is detected. Our previous work has suggested the cytokine receptor IL4Ra may play a role in contributing to metastasis in the alveolar subtype of rhabdomyosarcoma (aRMS), and thus could present a therapeutic target. The IL4 signaling axis has been characterized in various adult cancers as well; however, pediatric trials often follow similar adult trials and the role of the IL4Ra receptor has not been explored in the context of a mediator of metastasis in adult disease. Here, we demonstrate that the impact of IL4Ra blockade in an orthotopic allograft model of aRMS is not mediated by a macrophage response. We further examine the effect of IL4 blockade in adult colon, breast, and prostate cancers and find that inhibition of IL4Ra signaling modulates in vitro cell viability of HCT-116 colon carcinoma cells; however, this finding did not translate to an autocrine-related in vivo difference in tumor burden or lung metastasis. Our results suggest that if humanized IL4 mouse host strains are not available (or not ideal due to the need for immunosuppressing the host innate immune response for xenograft systems), then genetically-engineered mice and mouse allograft studies may be the best indicator of therapeutic targeting efficacy.

Original languageEnglish (US)
Pages (from-to)906-914
Number of pages9
JournalMolecular cancer therapeutics
Volume20
Issue number5
DOIs
StatePublished - May 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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