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The CD200-CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K.
- Source :
-
Cancer research [Cancer Res] 2021 Oct 01; Vol. 81 (19), pp. 5021-5032. Date of Electronic Publication: 2021 Jun 28. - Publication Year :
- 2021
-
Abstract
- The CD200-CD200R immunoregulatory signaling axis plays an etiologic role in the survival and spread of numerous cancers, primarily through suppression of antitumor immune surveillance. Our previous work outlined a prometastatic role for the CD200-CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T-cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200-CD200R axis important for cSCC metastasis, we conducted RNA sequencing profiling of infiltrating CD11B <superscript>+</superscript> Cd200R <superscript>+</superscript> cells isolated from CD200 <superscript>+</superscript> versus CD200-null cSCCs and identified the cysteine protease cathepsin K (Ctsk) to be highly upregulated in CD200 <superscript>+</superscript> cSCCs. CD11B <superscript>+</superscript> Cd200R <superscript>+</superscript> cells expressed phenotypic markers associated with myeloid-derived suppressor cell-like cells and tumor-associated macrophages and were the primary source of Ctsk expression in cSCC. A Cd200R <superscript>+</superscript> myeloid cell-cSCC coculture system showed that induction of Ctsk was dependent on engagement of the CD200-CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases, significantly blocked cSCC cell migration in vitro . Finally, targeted CD200 disruption in tumor cells and Ctsk pharmacologic inhibition significantly reduced cSCC metastasis in vivo . Collectively, these findings support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200R <superscript>+</superscript> infiltrating myeloid cells. SIGNIFICANCE: These findings highlight the relationship between CD200-CD200R and cathepsin K in cutaneous squamous cell carcinoma metastasis and suggest that either of these components may serve as a viable therapeutic target in this disease.<br /> (©2021 American Association for Cancer Research.)
- Subjects :
- Animals
Antigens, CD genetics
Carcinoma, Squamous Cell etiology
Carcinoma, Squamous Cell pathology
Cathepsin K metabolism
Disease Models, Animal
Fluorescent Antibody Technique
Genotype
Humans
Immunophenotyping
Membrane Glycoproteins genetics
Mice
Mice, Knockout
Mutation
Myeloid-Derived Suppressor Cells metabolism
Tumor Microenvironment genetics
Antigens, CD metabolism
Carcinoma, Squamous Cell metabolism
Cathepsin K genetics
Gene Expression Regulation, Neoplastic
Membrane Glycoproteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 81
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 34183355
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-20-3251