Immune therapies have had some success in the treatment of metastatic cancers. However, durable effects are limited in most patients despite the accumulation of intra-tumoral antigen-specific T cells. The tumor microenvironment (TME) is partly responsible for these failures through active blockade of local antitumor immune responses and facilitation of immune escape. Several immune modulating factors and/or cells are elicited within the TME, including the metalloproteinases, which enhance tumor growth and invasion through effects upon the tumor stroma, vasculature, and activation of factors such as TGF? and TNF?. Matrix metalloproteinase-2 (MMP-2), a gelatinase, is over-expressed in most cancers including melanoma, and its expression is associated with increased dissemination and poorer survival/prognosis. We recently found that enzymatically active MMP-2-conditioned dendritic cells (DCs) preferentially generate TH2 cells through mechanisms that inhibit IL-12 and up-regulate OX40L expression. Of note, only enzymatically active MMP-2 blocks IL-12 production, while both active and inactive conformations of MMP-2 induce up-regulation of OX40L. Strikingly, we also detected TILs in several patients that displayed MMP-2-specific responses. These responses were TH2-like and their presence was found to be inversely correlated with survival. MMP-2, therefore, acts simultaneously as an endogenous TH2 "conditioner" and tumor-associated antigen, which may explain, in part, the occurrence of unfavorable TH2 responses in melanoma. We previously characterized the mechanism responsible for IL-12 inhibition, which involves enzymatic cleavage of the type IIFN receptor, and consequent reduced STAT-1 phosphorylation and IL-12p35 transcription. We have since identified other novel immune mechanisms underlying MMP-2-dysregulation of DCs and the TME: MMP-2 directly triggers TLR-2 mediated signaling on both DCs and melanoma cell lines, inducing expression of OX40L and production of pro-inflammatory cytokines, respectively.
In Aim1, therefore, we will first identify the relevant TLR receptors and signaling pathways involved in OX40L up-regulation. The clinical relevance of this novel finding will be tested in animal models of melanoma (Aim 2). Finally, in Aim 3, we will evaluate whether MMP-2 directly modulates melanoma function and growth via TLR-mediated pathways.

Public Health Relevance

Matrix metalloproteinase-2 (MMP-2) is a protein that is over-expressed by most cancers and which modulates anti-tumor immune response. The proposed studies aim to characterize the mechanism underlying MMP-2- dependent OX40L over-expression, in order to determine how MMP-2 induces inflammatory TH 2 cells in vivo (Aim 1). Our data strongly indicate that TLR2 is the key receptor by which MMP-2 induces OX40L. We will next determine the physiological and clinical relevance of this MMP-2-mediated TH 2 cell skewing (Aim 2). Finally, in Aim 3, we will investigate the role of MMP-2 in the activation of melanoma associated-TLR2, based on our recent observation that melanoma cells express TLR2 and produce inflammatory cytokines upon MMP-2 exposure. Altogether, these studies will reveal how MMP-2 influences anti-tumor immunity towards melanoma and ascertain its direct effects upon tumor cell biology.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA180913-01A1
Application #
8777819
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029