Therapeutic targeting with DABIL-4 depletes myeloid suppressor cells in 4T1 triple-negative breast cancer model

Sadiya Parveen, Sumit Siddharth, Laurene S. Cheung, Alok Kumar, Jessica Shen, John R. Murphy, Dipali Sharma, William R. Bishai

Research output: Contribution to journalArticlepeer-review

Abstract

In many solid tumors including triple-negative breast cancer (TNBC), upregulation of the interleukin-4 receptor (IL-4R) has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential, and a Th2 response in the tumor microenvironment (TME). Since immunosuppressive cells in the TME and spleen including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) also express the IL-4R, we hypothesized that selective depletion of IL-4R-bearing cells in TNBC would result in the direct killing of tumor cells and the depletion of immunosuppressive cells and lead to an enhanced antitumor response. To selectively target IL-4R+ cells, we employed DABIL-4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL-4. As anticipated, DABIL-4 has potent cytotoxic activity against TNBC cells both in vitro and in vivo. We demonstrate in the murine 4T1 TNBC model that DABIL-4 significantly reduces tumor growth, splenomegaly, and lung metastases. Importantly, we also show that the administration of DABIL-4 results in the selective depletion of MDSCs, TAMs, and regulatory T cells in treated mice, with a concomitant increase in IFN-γ+ CD8 effector T cells in the TME. Since the 4T1 antitumor activity of DABIL-4 was largely diminished in IL-4R knockout mice, we postulate that DABIL-4 functions primarily as an immunotherapeutic by the depletion of MDSCs, TAMs, and regulatory T cells. NanoString analysis of control and treated tumors confirmed and extended these observations by showing a marked decline of mRNA transcripts that are associated with tumorigenesis and metastasis. In conclusion, we demonstrate that DABIL-4 targeting of both tumor and immunosuppressive host cells likely represents a novel and effective treatment strategy for 4T1 TNBC and warrants further study.

Original languageEnglish (US)
JournalMolecular oncology
DOIs
StateAccepted/In press - 2021

Keywords

  • DABIL-4
  • IL-4R
  • diphtheria fusion toxin
  • myeloid-derived suppressor cells
  • triple-negative breast cancer
  • tumor-associated macrophages

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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