Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.

Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for mast cells have also been documented. The impact of mast cells may be dependent on their activation status and mediator release in different tumors. Using an orthotopic melanoma model in wild-type C57BL/6 and mast cell-deficient KitW-sh/W-sh mice and a complementary Matrigel–tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam3CSK4)-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam3CSK4 was restored in KitW-sh/W-sh mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam3CSK4 activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. Mast cell-mediated anticancer properties were multifaceted. Direct antitumor effects in vitro and decreased angiogenesis and recruitment of NK and T cells in vivo were observed. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo. Unlike other immune cells, mast cells are relatively radioresistant making them attractive candidates for combined treatment modalities. This study has important implications for the design of immunotherapeutic strategies and reveals, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo.

Studies aimed at elucidating the immunological and prognostic significance of HLA-DR expression on breast carcinoma cells have yielded contradictory results. To expand on previous studies, we have investigated the associations of tumor cell expression of HLA-DR and its related co-chaperones, invariant chain (Ii) and HLA-DM, with infiltrating inflammatory cells, in situ cytokine mRNA levels and prognosis and outcome in 112 breast carcinoma patients with a median follow-up of 59 months. While the majority of HLA-DR+ tumors co-express Ii, only a minority express HLA-DM. Tumor cell expression of HLA-DR and co-chaperones positively associated with both infiltrating CD4+ and CD8+ T-cell subsets (P < 0.01). Expression of HLA-DR and Ii associated with decreased estrogen receptor alpha levels and younger age at diagnosis, suggesting a role for hormones in the control of HLA class II expression in breast carcinoma. Patients with DR+Ii+DM- tumors had markedly decreased recurrence-free and disease-specific survival as compared with patients with DR+Ii+DM+ tumors (P < 0.05) and HLA-DR/co-chaperone expression was an independent predictor of survival by multivariate Cox regression analysis, controlling for standard prognostic indicators. Tumors that co-express HLA-DR, Ii and HLA-DM have increased levels of IFN-gamma, IL-2 and IL-12 mRNA, suggesting improved survival of patients with DR+Ii+DM+ tumors may be attributable to Th1-dominated immunity. We conclude that expression of determinants of the immune response by tumor cells may influence breast tumor progression and patient outcome.

Despite low levels of infection, human mast cells produce multiple chemokines in response to RSV through mechanisms that include responses to type I interferons. Such mast cell responses might enhance effector cell recruitment during RSV-induced disease.

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Histamine receptor 2 (H2) antagonists are widely used clinically for the control of gastrointestinal symptoms, but also impact immune function. They have been reported to reduce tumor growth in established colon and lung cancer models. Histamine has also been reported to modify populations of myeloid-derived suppressor cells (MDSCs). We have examined the impact of the widely used H2 antagonist ranitidine, on both myeloid cell populations and tumor development and spread, in three distinct models of breast cancer that highlight different stages of cancer progression. Oral ranitidine treatment significantly decreased the monocytic MDSC population in the spleen and bone marrow both alone and in the context of an orthotopic breast tumor model. H2 antagonists ranitidine and famotidine, but not H1 or H4 antagonists, significantly inhibited lung metastasis in the 4T1 model. In the E0771 model, ranitidine decreased primary tumor growth while omeprazole treatment had no impact on tumor development. Gemcitabine treatment prevented the tumor growth inhibition associated with ranitidine treatment. In keeping with ranitidine-induced changes in myeloid cell populations in non-tumor-bearing mice, ranitidine also delayed the onset of spontaneous tumor development, and decreased the number of tumors that developed in LKB1−/−/NIC mice. These results indicate that ranitidine alters monocyte populations associated with MDSC activity, and subsequently impacts breast tumor development and outcome. Ranitidine has potential as an adjuvant therapy or preventative agent in breast cancer and provides a novel and safe approach to the long-term reduction of tumor-associated immune suppression.

The biologic and prognostic significance of HLA-DR expression and T-cell infiltration in breast carcinoma are presently controversial. To test the hypothesis that these factors are influenced by particular HLA-DRB alleles, 52 breast tumor samples, composed of 26 DRB1*04 and 26 non-DRB1*04 tumors, were assessed using immunohistochemistry for expression of DR and its associated invariant chain (Ii) and for infiltrating CD3 ؉ T cells. While DR expression by tumor cells was significantly associated with T-cell infiltration, DRB1*04 tumors were more frequently DR ؉ Ii ؉ and contained smaller CD3 ؉ infiltrates than non-DRB1*04 tumors. This difference was largely attributable to DRB1*07 tumors, which were typically DR ؊ Ii ؊ , although they contained similar numbers of T cells to DR ؉ Ii ؉ tumors. Further analysis of DR ؉ tumors using allotype discriminating antibodies revealed that DRB1*04 alleles were always expressed, while non-DRB1*04 alleles were inconsistently expressed. The results of this study provide the first reported evidence that DRB alleles influence DR expression and T-cell infiltration in breast carcinoma and suggest that multiple factors contribute to DR expression. Ongoing studies aimed at elucidating the molecular and immunologic mechanisms controlling differential DR expression and implications for prognosis and outcome should further our understanding of the antitumor immune response and evasion strategies employed by tumor cells. © 2004 Wiley-Liss, Inc. Key words: HLA-DR expression; HLA-DRB alleles; T-cell infiltration; breast carcinoma; invariant chainA prerequisite for tumor eradication by CD8 ϩ cytolytic T cells is recognition of tumor antigen presented by HLA class I molecules on the tumor cells and this is reflected by the numerous studies showing loss or downregulation of HLA class I on established tumors. 1,2 Optimal antitumor immunity also requires participation of CD4 ϩ T cells, which recognize tumor peptides presented by HLA class II molecules (HLA-DR, -DP, -DQ). [3][4][5] However, the importance of HLA class II expression on breast carcinoma cells and implications for antitumor immunity are currently unclear. Unlike HLA class I, HLA class II molecules are not normally present on resting epithelial cells, although they are detected de novo in the lactating breast and in a subset of breast carcinomas. 6 They can also be induced in vitro on many cell types, including breast cancer cell lines, by interferon-␥ (IFN-␥) 7,8 and other immunomodulators, 9,10 suggesting that in situ expression on carcinoma cells may be regulated by cytokines and/or hormones. Antigen presentation by HLA class II ϩ breast cancer cells, which lack costimulatory molecules typically found on professional antigen presenting cells (APCs), could potentially induce T-cell anergy. However, reports of direct recognition of tumor cells by HLA class II-restricted CD4 ϩ T cells 11,12 suggest that HLA class II ϩ tumor cells play an important role in determining the outcome of an antitumor immune response.Studies investigating e...

BackgroundMast cells are resident immune effector cells, often studied in the context of allergic disease. Found in substantial numbers at sites of potential infection they are increased at sites of angiogenesis and can be pivotal for the sensing and clearance of a variety of pathogens. Interferons (IFNs) are cytokines that are critical for host defence against intracellular pathogens. Increased levels of IFNs are observed during viral infection and in autoimmune diseases. IFNs are also widely used therapeutically and have been examined in the therapy of severe asthma.ObjectiveTo define the selective human mast cell cytokine and chemokine response following activation with type I or type II IFN's.MethodsThe ability of both IFNα2 and IFNγ to induce cytokine production by human cord blood‐derived mast cells was examined in vitro. Cytokine and chemokine production at 6 and 24 h was assessed by multiplex protein analysis. Degranulation was assessed by β‐hexosaminidase release. Mast cells were also treated with reovirus or respiratory syncytial virus and their production of CXCL10, IL‐1 receptor antagonist (IL‐1Ra), and vascular endothelial growth factor (VEGF) examined after 24 h.ResultsIn addition to increased expression of classical IFN response genes, such as CXCL10, small but significant increases in CCL5 and IL‐17 production were observed following IFN activation. Notably, human mast cells produced both VEGF and IL‐1Ra in a dose dependent manner. These responses occurred in the absence of mast cell degranulation by a mechanism consistent with classical IFN signaling. Both reovirus and respiratory syncytial virus infection of mast cells, were also associated with IFN‐dependent IL‐1Ra expression.Conclusion and Clinical RelevanceOur findings demonstrate that IFNs have profound impact on cytokine and chemokine expression by human mast cells, alone or in the context of viral infection. Mast cell VEGF and IL‐1Ra responses to IFNs could impact the regulation of local inflammatory responses and subsequent tissue remodeling.