Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen

Ugel, Stefano; Peranzoni, Elisa; Desantis, Giacomo; Chioda, Mariacristina; Walter, Steffen; Weinschenk, Toni; Ochando, Jordi; Cabrelle, Anna; Mandruzzato, Susanna; Bronte, Vincenzo

doi:10.1016/j.celrep.2012.08.006

Cited by 191 publications

(245 citation statements)

References 41 publications

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“…The suppression assay demonstrated that the in vitro inhibitory function of graft infiltrating Ly6Clo macrophages is confined to the proliferating S/G2/M subset. This is consistent with our previous collaborative finding, which demonstrated that suppressive monocytic-derived cells from tumor bearing mice are highly proliferative (24). …”

Section: Resultssupporting

confidence: 94%

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Braza

Conde

Garcia

et al. 2018

American Journal of Transplantation

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Summary The colony-stimulating factor 1 (CSF1) regulates the differentiation and function of tissue macrophages and determines the outcome of the immune response. The molecular mechanisms behind CSF1-mediated macrophage development remain to be elucidated. Here we demonstrate that neutrophil-derived CSF1 controls macrophage polarization and proliferation, which is necessary for the induction of tolerance. Inhibiting neutrophil production of CSF1 or preventing macrophage proliferation, using targeted nanoparticles loaded with the cell cycle inhibitor simvastatin, abrogates the induction of tolerance. These results provide new mechanistic insights into the developmental requirements of tolerogenic macrophages and identify CSF1 producing neutrophils as critical regulators of the immunological response.

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Section: Resultssupporting

confidence: 94%

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Braza

Conde

Garcia

et al. 2018

American Journal of Transplantation

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“…6C), while leaving the Gr1 hi , Gr1 lo , and Gr1 À cells unaffected compared with contraimmunized and control mice. Interestingly, Gr1 int MDSCs were recently shown to be the most immunosuppressive MDSCs in tumor-bearing mice (36). Furthermore, we observed that significantly more MHCII þ -expressing CD11b þ Gr1 þ MDSCs infiltrated the tumors of tdLN-targeted (ipsi) mice compared with control and non-tdLN-targeted (contra) mice, suggesting maturation of MDSCs (Fig.…”

Section: Targeting the Tdln With Nanoparticle-conjugated Ova And Cpg supporting

confidence: 49%

“…6). While we previously showed that tumorinfiltrating monocytic MDSCs are NP þ , delivering our model cancer vaccine to the tdLN decreased the number of tumorresident Gr1 int MDSCs, which are described as monocytic and the most immunosuppressive subset, and led to MDSC maturation, thus making them less suppressive (21,36,48). CpG has been shown to affect the phenotype of MDSCs, especially monocytic MDSCs, in tumor-bearing mice, but at much higher CpG doses than we used here (32,49).…”

Section: Discussionmentioning

confidence: 94%

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

172

133

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The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in nontumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8 þ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436-47. Ó2014 AACR.

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“…Because the key role of the spleen for tumor-induced tolerance mediated by MDSCs has been recently demonstrated in a thymoma and mammary mouse model (19), we focused our attention on the splenic microenvironment of AOM/DSS-treated tumor-bearing mice, in which the two cell populations also were found in close proximity (Fig. 1F).…”

Section: Mast Cells Potentiate Monocytic Mdsc-suppressive Properties mentioning

confidence: 99%

Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

Danelli

Frossi

Gri

et al. 2015

Cancer Immunology Research

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Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cellto-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b þ Gr1 þ immature MDSCs and the recruitment of protumoral mast cells at the tumor site. Using ex vivo analyses, we showed that mast cells have the ability to increase the suppressive properties of spleenderived monocytic MDSCs, through a mechanism involving IFNg and nitric oxide production. In addition, we demonstrated that the CD40:CD40L cross-talk between the two cell populations is responsible for the instauration of a proinflammatory microenvironment and for the increase in the production of mediators that can further support MDSC mobilization and tumor growth. In light of these results, interfering with the MDSC:mast cell axis could be a promising approach to abrogate MDSC-related immune suppression and to improve the antitumor immune response. Cancer Immunol Res; 3(1); 85-95. Ó2014 AACR.

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Immune Tolerance to Tumor Antigens Occurs in a Specialized Environment of the Spleen

Cited by 191 publications

References 41 publications

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Mast Cells Boost Myeloid-Derived Suppressor Cell Activity and Contribute to the Development of Tumor-Favoring Microenvironment

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