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

Autor: Dipali Sharma, John R. Murphy, Jessica Shen, Sadiya Parveen, Sumit Siddharth, Laurene S. Cheung, William R. Bishai, Alok Kumar
Rok vydání: 2021
Předmět:
0301 basic medicine
Cancer Research
Myeloid
tumor‐associated macrophages
Apoptosis
Cell Count
Triple Negative Breast Neoplasms
medicine.disease_cause
IL‐4R
Metastasis
Mice
0302 clinical medicine
Cytotoxic T cell
Molecular Targeted Therapy
Research Articles
RC254-282
Triple-negative breast cancer
Mice
Knockout
Mice
Inbred BALB C
Chemistry
Interleukin-4 Receptor alpha Subunit
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
General Medicine
DABIL‐4
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Female
Research Article
Recombinant Fusion Proteins
Antineoplastic Agents
Adenocarcinoma
03 medical and health sciences
Cell Line
Tumor
Genetics
medicine
Animals
Humans
myeloid‐derived suppressor cells
Tumor microenvironment
Myeloid-Derived Suppressor Cells
diphtheria fusion toxin
medicine.disease
Xenograft Model Antitumor Assays
triple‐negative breast cancer
030104 developmental biology
Cancer research
Myeloid-derived Suppressor Cell
Interleukin-4
Carcinogenesis
CD8
Zdroj: Molecular Oncology, Vol 15, Iss 5, Pp 1330-1344 (2021)
Molecular Oncology
ISSN: 1878-0261
1574-7891
DOI: 10.1002/1878-0261.12938
Popis: 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.
Treatment with the interleukin‐4 diphtheria fusion toxin protein (DABIL‐4) targeted and killed both tumor cells and the immunosuppressive cell populations of the tumor microenvironment. DABIL‐4 treatment in a murine triple‐negative breast cancer (TNBC) model reduced MDSCs, tumor‐associated macrophages, and Treg cell populations and inhibited both tumor growth and metastasis. DABIL‐4 targeting likely represents a novel and effective treatment strategy for TNBC.
Databáze: OpenAIRE
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