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Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Taku Fujimura1, Aya Kakizaki1, Yumi Kambayashi1

  • 1Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Experimental Dermatology
|August 24, 2017
PubMed

Insights

Dacarbazine (DTIC) and vincristine (VCR) reduce immune suppressors PD-L1 and CCL22 in melanoma. This suggests a mechanism for how DTIC, ACNU, and VCR chemotherapy may enhance anti-melanoma immune responses.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) maintain the tumor microenvironment.
  • Malignant melanoma is treated with cytotoxic drugs like dacarbazine (DTIC), nimustine hydrochloride (ACNU), and vincristine (VCR), but their immunomodulatory mechanisms are unclear.
  • M2 macrophages, a common TAM type, promote tumor development.

Purpose of the Study:

  • To investigate the immunomodulatory effects of DTIC, ACNU, and VCR on human monocyte-derived M2 macrophages.
  • To elucidate the impact of these drugs on immune checkpoint molecules and chemokines.
  • To understand potential mechanisms of DAV combination chemotherapy in melanoma treatment.

Main Methods:

  • Assessed mRNA expression and protein production of PD-L1 and CCL22 in M2 macrophages treated with DTIC, ACNU, and VCR.
  • Utilized flow cytometry to confirm PD-L1 expression changes.
  • Validated findings in the B16F10 mouse melanoma model in vivo.

Main Results:

  • DTIC and VCR significantly decreased PD-L1 mRNA expression and protein levels.
  • DTIC significantly reduced CCL22 mRNA expression and production, potentially inhibiting Treg recruitment.
  • In vivo studies confirmed decreased PD-L1 and CCL22, leading to restored T-cell proliferation.

Conclusions:

  • DTIC and VCR modulate M2 macrophages by reducing PD-L1 expression.
  • DTIC may suppress melanoma by decreasing CCL22 and Treg recruitment.
  • These findings suggest a novel immunomodulatory mechanism for DAV combination chemotherapy in melanoma treatment.
Keywords:
chemokine productioncytotoxic antimelanoma drugsimmunomodulationtumor-associated macrophages

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