Abstract
Expression of surface NKG2D ligand MIC on tumor cells is deemed to stimulate NK and co-stimulate CD8 T cell anti-tumor immunity. Human cancer cells however frequently adopt a proteinase-mediated shedding strategy to generate soluble MIC (sMIC) to circumvent host immunity. High levels of sMIC have been shown to correlate with advanced disease stages in cancer patients. The underlying mechanism is currently understood as systemic downregulation of NKG2D expression on CD8 T and NK cells and perturbing NK cell periphery maintenance. Herein we report a novel mechanism by which sMIC poses immune suppressive effect on host immunity and tumor microenvironment. We demonstrate that sMIC facilitates expansion of myeloid-derived suppressor cells (MDSCs) and skews macrophages to the more immune suppressive alternative phenotype through activation of STAT3. These findings further endorse that sMIC is an important therapeutic target for cancer immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0110-z) contains supplementary material, which is available to authorized users.
Highlights
Expression of surface NKG2D ligands on tumor cells is well proven to provoke tumor rejection through activation of NK and CD8 T cells in experimental animal models [1,2,3]
Results and discussion soluble MICB (sMICB) increases frequency of myeloid-derived suppressor cells (MDSCs) and arginase I+ cells in bi-transgenic transgenic adenocarcinoma mouse prostate (TRAMP)/MIC mice MIC is not expressed in rodents, which limits the potential to study the global impact of tumor-derived soluble MIC (sMIC) on host anti-tumor immunity in vivo
The TRAMP/MICB model highly resembles human cancer patients in the kinetics of oncogenesis and tumor immunity in that MIC expression is concurrent with oncogenic events and MIC shedding correlates with tumor progression [13]
Summary
Expression of surface NKG2D ligands on tumor cells is well proven to provoke tumor rejection through activation of NK and CD8 T cells in experimental animal models [1,2,3]. Human cancers broadly evade this mechanism by adopting a protease-dependent shedding mechanism to generate soluble NKG2D ligands [4,5,6]. Elevated shedding of cell surface MIC has been associated with advanced disease stages and metastasis in many types of epithelial cancers [4,7,8,9,10]. It is well accepted that tumor-derived soluble MIC (sMIC) is a negative immune regulator in cancer patients, the underlying mechanisms are not fully understood. Multiple mechanisms have been uncovered by which soluble sMIC insults the immune system.
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