Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

Ko, Hyun–Jeong; Lee, Jung Mi; Kim, Yeon Jeong; Kim, Yun-Sun; Lee, Kyoo‐A; Kang, Chang–Yuil

doi:10.4049/jimmunol.0802430

Cited by 119 publications

(123 citation statements)

References 61 publications

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“…For example, activated NKT cells have been shown to induce the conversion of MDSCs to immunogenic APCs, presumably by producing soluble factors from activated NKT cells (40). It has also been shown that Gr-1 + CD11b + F4/80 + macrophagelike cells suppressed T cell proliferation, but that Gr-1 + CD11b + F4/ 80 2 neutrophil-like cells were not suppressive in a tumor-bearing mouse model (41).…”

Section: Discussionmentioning

confidence: 99%

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Tomihara

Guo

Shin

et al. 2010

The Journal of Immunology

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Both innate and adaptive immune systems are considered important for cancer prevention, immunosurveillance, and control of cancer progression. It is known that, although both systems initially eliminate emerging tumor cells efficiently, tumors eventually escape immune attack by a variety of mechanisms, including differentiation and recruitment of immunosuppressive CD11b+Gr-1+ myeloid suppressor cells into the tumor microenvironment. However, we show that CD11b+Gr-1+ cells found in ascites of epithelial ovarian cancer-bearing mice at advanced stages of disease are immunostimulatory rather than being immunosuppressive. These cells consist of a homogenous population of cells that morphologically resemble neutrophils. Moreover, like dendritic cells, immunostimulatory CD11b+Gr-1+ cells can strongly cross-prime, augmenting the proliferation of functional CTLs via signaling through the expression of costimulatory molecule CD80. Adoptive transfer of these immunostimulatory CD11b+Gr-1+ cells from ascites of ovarian cancer-bearing mice results in the significant regression of s.c. tumors even without being pulsed with exogenous tumor Ag prior to adoptive transfer. We now show for the first time that adaptive immune responses against cancer can be augmented by these cancer-induced granulocyte-like immunostimulatory myeloid (CD11b+Gr-1+) cells, thereby mediating highly effective antitumor immunity in an adoptive transfer model of immunity.

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Section: Discussionmentioning

confidence: 99%

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Tomihara

Guo

Shin

et al. 2010

The Journal of Immunology

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“…24,42,43 However, the relationship between NKT cells and MDSCs is unclear as NKT cells have been shown to suppress or promote MDSC accumulation and activity in different settings. 29,37,[44][45][46] We prepared hematoxylin and eosin-stained cytospins of peripheral blood samples to characterize the leukocyte populations. Compared to na€ ıve controls, tumor bearing mice had significantly higher numbers of granulocytic cells with few lymphocytes and monocytes (Fig.…”

Section: Glycolipid Treatments Reduce Metastasismentioning

confidence: 99%

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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Metastatic lesions are responsible for over 90% of breast cancer associated deaths. Therefore, strategies that target metastasis are of particular interest. This study examined the efficacy of natural killer T (NKT) cell activation as a postsurgical immunotherapy in a mouse model of metastatic breast cancer. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with NKT cell activating glycolipid antigens (a-GalCer, a-CGalCer or OCH) or a-GalCer-loaded dendritic cells (DCs). Low doses of glycolipids transiently reduced metastasis but did not increase survival. A high dose of a-GalCer enhanced overall survival, but was associated with increased toxicity and mortality at early time points. Treatment with a-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes in »45% of mice. However, survival was not increased further by additional DC treatments or co-transfer of expanded NKT cells. NKT cell activation via glycolipid-loaded DCs decreased the frequency and immunosuppressive activity of myeloid derived suppressor cells (MDSCs) in tumor-resected mice. In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation. NKT cell activation enhanced antitumor immunity in tumor-resected mice, increasing 4T1-specific cytotoxic responses and IFNg production from natural killer (NK) cells and CD8 C T cells. Consistent with increased tumor immunity, mice surviving to day 150 were resistant to a second tumor challenge. This work provides a clear rationale for manipulating NKT cells to target metastatic disease.

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“…8 The purity of CD11b þ cells was more than 90% in total viable cells and expressed high or intermediate levels of Gr-1 (data not shown). OT-I or DO11.10 cells (3 Â 10 5 /well) were stimulated with OVA protein (grade V; Sigma-Aldrich, St. Louis, MO)-pulsed splenocytes and cocultured with isolated CD11b þ cells for 3 days.…”

Section: In Vitro T Cell Suppression Measured By Thymidine Incorporatmentioning

confidence: 94%

“…8 Thus, we checked whether MDSCs generated in the absence of Myd88 signaling have enhanced expression of costimulatory molecules, including CD40, CD80 and CD86, compared with those generated in WT mice. To our surprise, expression of CD40, CD80 and CD86 on MDSCs was significantly higher in Myd88 À/À mice than in WT mice, with CD40 expression showing the most significant increase (Figs.…”

Section: Myd88 2/2 Mdscs Acquired Immunogenic Characteristicsmentioning

confidence: 99%

“…5,6 Myeloid-derived suppressor cells (MDSCs) accumulate in the tumor, peripheral blood, spleen and bone marrow of tumorbearing mice and humans with cancer. 7,8 MDSCs are known to elicit immunosuppressive functions against many kinds of effectors including CD4 þ T cells and CD8 þ T cells. [9][10][11][12] Furthermore, they facilitate the generation of regulatory T cells and contribute to tumor angiogenesis.…”

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confidence: 99%

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Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

Hong

Chang

Lee

et al. 2012

Intl Journal of Cancer

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Myd88 is an important adaptor molecule for the activation of NADPH oxidase and arginase-1, which are responsible for the suppressive function of myeloid-derived suppressor cells (MDSCs). When wild-type and Myd88 2/2 mice were subcutaneously injected with CT26 colon cancer cells expressing human Her-2/neu, tumor growth was retarded in Myd88 2/2 mice than in wild-type mice. Although the generation of CD11b 1 Gr-1 1 MDSCs was less in Myd88 2/2 mice than in wild-type mice, Myd88 2/2 mice having tumor masses still had significant quantities of MDSCs, suggesting that MDSC generation might be independent of Myd88 signaling. However, MDSCs obtained from tumor-bearing Myd88 2/2 mice failed to suppress antigenspecific proliferation of CD8 1 T cells and CD4 1 T cells, whereas MDSCs from wild-type mice significantly suppressed both types of T cells. Consistent with this, we found that the levels of costimulatory molecules and MHC class II were significantly increased in MDSCs obtained from Myd88 2/2 mice compared with wild-type mice after tumor challenge. Furthermore, CD4 1 T cells residing in tumor-draining lymph nodes of Myd88 2/2 mice secreted more TNF-a than those of wild-type mice. Finally, the blockade of Myd88 signaling by treatment with Myd88 inhibitory peptide, during later tumor stages, significantly inhibited the growth of immunogenic tumors. Overall, these data suggest that signaling through the Myd88 adaptor molecule is critical for the direct suppressive function of MDSCs and approaches to block Myd88-mediated signaling in MDSCs might be effective to inhibit the immunosuppressive function of MDSCs.

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Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

Cited by 119 publications

References 61 publications

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid‐derived suppressor cells

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