Cyclophosphamide promotes chronic inflammation-dependent immunosuppression and prevents antitumor response in melanoma

J Invest Dermatol. 2013 Jun;133(6):1610-9. doi: 10.1038/jid.2012.444. Epub 2012 Dec 6.

Abstract

Low-dose cyclophosphamide (CP) therapy induces immunogenic tumor cell death and decreases regulatory T cell (Treg) numbers in mice with transplantable tumors. Using the ret transgenic murine melanoma model that resembles human melanoma, we detected no beneficial antitumor effects with such treatment, despite a decrease in Tregs. On the contrary, low-dose CP enhanced the production of chronic inflammatory mediators in melanoma lesions associated with increased accumulation of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), which exhibit elevated suppressive activity and nitric oxide (NO) production as well as inhibition of T-cell proliferation. Moreover, the frequencies of CD8(+) T cells in the tumors and their ability to produce perforin were decreased. To study whether the observed CP-induced MDSC expansion and activation also occurs under chronic inflammatory tumor-free conditions, mice exhibiting chronic inflammation were treated with CP. Similar to tumor-bearing mice, CP-treated inflamed mice displayed elevated levels of MDSCs with enhanced production of NO, reactive oxygen species, and a suppressed in vivo natural killer (NK) cell cytotoxic activity indicating CP effects on the host immune system independent of the tumor. We suggest that melanoma therapy with low-dose CP could be efficient only when combined with the neutralization of MDSC immunosuppressive function and chronic inflammatory microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Cyclophosphamide / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Immunosuppression / methods*
  • Immunosuppressive Agents / pharmacology
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / pathology
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Cells / cytology
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Proto-Oncogene Proteins c-ret / genetics
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Immunosuppressive Agents
  • Cyclophosphamide
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse