Mesenchymal Stromal Cells Expressing ErbB-2/neu Elicit Protective Antibreast Tumor Immunity In vivo, Which Is Paradoxically Suppressed by IFN-γ and Tumor Necrosis Factor-α Priming

Abstract

It is unknown whether mesenchymal stromal cells (MSC) can regulate immune responses targeting tumor autoantigens of low immunogenicity. We tested here whether immunization with MSC could break immune tolerance towards the ErbB-2/HER-2/neu tumor antigen and the effects of priming with IFN-γ and tumor necrosis factor-α (TNF-α) on this process. BALB/c-and C57BL/6-derived MSC were lentivirally transduced to express a kinase-inactive rat neu mutant (MSC/Neu). Immunization of BALB/c mice with nontreated or IFN-γ-primed allogeneic or syngeneic MSC/Neu induced similar levels of anti-neu antibody titers; however, only syngeneic MSC/Neu induced protective neu-specific CD8 + T cell responses. Compared to immunization with nontreated or IFN-γ-primed syngeneic MSC/Neu, the number of circulating neu-specific CD8 + T cells and titers of anti-neu antibodies were observed to be decreased after immunizations with IFN-γ-plus TNF-α-primed MSC/Neu. In addition, syngeneic MSC/Neu seemed more efficient than IFN-γ-primed MSC/Neu at inducing a protective therapeutic antitumor immune response resulting in the regression of transplanted neu-expressing mammary tumor cells. In vitro antigen-presenting cell assays performed with paraformaldehyde-fixed or live MSC showed that priming with IFN-γ plus TNF-α, compared to priming with IFN-γ alone, increased antigen presentation as well as the production of immunosuppressive factors. These data suggest that whereas MSC could effectively serve as antigen-presenting cells to induce immune responses aimed at tumor autoantigens, these functions are critically regulated by IFN-γ and TNF-α. Cancer Res; 70(20); 7742-7. ©2010 AACR.

LIGHT Delivery to Tumors by Mesenchymal Stem Cells Mobilizes an Effective Antitumor Immune Response

“…showed that MSCs expressing ErbB-2/neu elicited full protective antitumor immunity in vivo (43). In line with the above findings, we observed that MSC-L can prime antitumor immunity to control tumor.…”

Stem Cells and Cell Therapies in Lung Biology and Lung Diseases

“…These cells function, in part, by providing a supportive stroma for the cancers and/or by participating in tumor vascularization (145)(146)(147)(148)(149)(150)(151)(152)(153)(154)(155)(156)(157)(158)(159). In contrast, MSCs and EPCs have been demonstrated to home to areas of tumor development, and engineered EPCs and MSCs, as well as Hematopoietic Stem Cells (HSCs), have been used to suppress tumor growth in mouse tumor models of primary lung cancers, metastatic lung cancers, and of other cancers metastatic to the lung (148,(160)(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177)(178)(179). Cell based treatment may thus be useful in lung cancer therapeutics.…”

“…Although the frequency of MSCs in the adult bone marrow is low (less than 0.1%), once isolated from bone marrow or from other tissues, MSCs can be expanded ex vivo, which makes it possible to manufacture these cells for potential therapeutic purposes. MSCs can also be relatively easily transduced or genetically manipulated to deliver or to secrete selected disease-modifying molecules (148,(161)(162)(163)(164)(165)(166)(167)(168)(169)(170)(171)(172)(173)(174)(175)(176)(177)(178)(179)(388)(389)(390). Overall, these properties of MSCs make them an attractive potential therapeutic tool as vectors for delivery of disease-specific treatment substances or as immunomodulatory agents.…”

Regulation of the inflammatory profile of stromal cells in human breast cancer: prominent roles for TNF-α and the NF-κB pathway

“…In contrast to tumor-cytotoxic effects caused by acute local TNF-α administration, chronic and persistent presence of TNF-α in tumors has strong pro-tumoral effects in many cancers [19-21]. Accordingly, inhibition of TNF-α or its receptors has prominent anti-tumor effects in animal models of breast cancer [22-29]. In parallel, major causative pro-tumoral roles were attributed to IL-1β in breast cancer via angiogenesis and matrix-remodeling activities [30-37].…”