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2016 ; 65
(10
): 1261-8
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Modulation of innate immunity in the tumor microenvironment
#MMPMID27344341
Gonzalez-Gugel E
; Saxena M
; Bhardwaj N
Cancer Immunol Immunother
2016[Oct]; 65
(10
): 1261-8
PMID27344341
show ga
A recent report from the Center for Disease Control identified melanoma as being
among the highest causes of cancer-related mortalities in the USA. While
interventions such as checkpoint blockade have made substantial impact in terms
of improving response rates and overall survival, a significant number of
patients fail to respond to treatment or become resistant to therapy. A better
understanding of the tumor microenvironment in these patients becomes imperative
for identifying immune suppressive mechanisms that impact the development of
effective anti-tumor immune responses. We have investigated innate immune cells
(dendritic cells, NK cells) in the tumor microenvironment (TME) in order to
devise effective targeted anticancer immune therapies. We find that matrix
metalloproteinase-2 (MMP-2), secreted from melanoma cells and stromal cells,
cleaves IFNAR1 and stimulates TLR-2 on dendritic cells (DC) within the TME. Both
these events independently culminate in programing the DCs to promote
pro-tumorigenic TH2 T cell differentiation. In addition, we have shown that NK
cells become functionally exhausted in melanoma patients. We identified the
expression of Tim-3 as one of the factors responsible for NK cell exhaustion and
showed that anti-Tim3 antibodies partially reversed this exhaustion. We have
initiated local intervention strategies such as intra-tumoral administration of
DC activating Poly-ICLC and compared the efficacy of different TLR agonists and
melanoma antigens for use as combination tumor vaccine in clinical trials. Such
approaches will provide a unique insight into tumor biology and will facilitate
in development of highly effective and cell type-specific immune therapies.
|*Tumor Microenvironment
[MESH]
|Animals
[MESH]
|Dendritic Cells/*immunology
[MESH]
|Hepatitis A Virus Cellular Receptor 2/genetics/*metabolism
[MESH]
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