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MHC class II antigen presentation by tumoral lymphatics is required for tumor specific signature and suppressive functions of Tregs

ABSTRACT: A number of solid malignancies triggers lymphangiogenesis, facilitating metastasis. Recent studies further indicate that tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment. Here, we have investigated the ability of tumor-associated lymphatic endothelial cells (LECs) to function as MHC class II restricted antigen-presenting cells in the regulation of anti-tumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we show that tumor LECs upregulate MHCII and the MHCII antigen processing machinery, and promote Treg expansion ex vivo. Using mice with a LEC-restricted lack of MHCII expression, we demonstrate that tumor growth is severely impaired, whereas tumor-infiltrating T effector cells are increased. Reduction of tumor growth and reinvigoration of tumor-specific T cell responses both result from alterations of the tumor-infiltrating regulatory T cell (Treg) transcriptome and phenotype. Treg suppressive functions are consequently profoundly altered in tumors lacking MHCII in LECs. No difference in effector T cell responses or Treg phenotype and functions were observed in tumor-draining lymph nodes, indicating that MHCII restricted antigen presentation by LECs is required locally in the tumor microenvironment (TME) to confer potent suppressive functions to Tregs. Altogether, our study advocates a role for MHCII-restricted antigen-presenting tumor LECs that function as a local brake, dampening tumor T cell immunity and promoting intratumoral Treg suppressive functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE168609 | GEO | 2024/03/01

REPOSITORIES: GEO

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Project description:Regulatory T (Treg) cells play an important role in the induction and maintenance of peripheral tolerance. Treg cells also suppress a variety of other immune responses, including anti-tumor and alloimmune responses. We have previously reported that tumor-activated Treg cells express granzyme B and that granzyme B is important for Treg cell-mediated suppression of anti-tumor immune responses (GSE13409). Here, we report that allogeneic mismatch also induces the expression of granzyme B. Granzyme B-deficient mice challenged with fully mismatched allogeneic P815 mastocytoma cells have markedly improved survival compared to WT and other granzyme- or perforin-deficient mice, suggesting an immunoregulatory role for granzyme B in this setting. Treg cells harvested from the tumor environment of P815-challenged mice express granzyme B. Treg cells also express granzyme B in vitro during mixed lymphocyte reactions and in vivo in a mouse model of graft-versus-host disease (GVHD). However, in contrast to findings from our previously published tumor model, granzyme B is not required for the suppression of effector T cell (Teff) proliferation in in vitro Treg suppression assays stimulated by either Concanavalin A or allogeneic antigen presenting cells. Additionally, in an ex vivo assay, sort-purified in vivo-activated CD4+Foxp3+ Treg cells from mice with active GVHD -- under conditions known to induce granzyme B expression in Treg cells -- suppressed Teff cell proliferation in a granzyme B-independent manner. Adoptive transfer of naive granzyme B-deficient CD4+CD25+ Treg cells into a mouse model of GVHD rescued hosts from lethatlity equivalently to naive wild-type Treg cells. Serum analysis of GVHD-associated cytokine production in these recipients also demonstrated that Treg cells suppressed production of IL-2, IL-4, IL-5, GM-CSF, and IFN-gamma in a granzyme B-independent manner. In order to determine whether the context in which Treg cells are activated alters the intrinsic properties of Treg cells, we used Foxp3 reporter mice to obtain gene expression profiles of CD4+Foxp3+ Treg cells purifed from naive resting spleens, spleens from mice with acute GVHD, and from ascites fluid of mice challenged intraperitoneally with allogeneic P815 tumor cells. Unsupervised analyses revealed distinct activation signatures of Treg cells among the 3 experimental groups. Taken together, these findings demonstrate that granzyme B is not required for Treg cell-mediated suppression of GVHD, which is in contrast to what we have previously reported for Treg cell function in the setting of tumor challenge. Cell intrinsic differences could partially account for these differential phenotypes. These data also suggest the therapeutic potential of targeting specific Treg cell suppressive functions in order to segregate GVHD and graft-versus-tumor effector functions. Experiment Overall Design: Six replicates of Naive CD4+Foxp3+ Treg cells were purified from resting spleens, five replicates of allogeneic tumor-activated Treg cells and three samples of GVHD-activated Treg cells. Experiment Overall Design: Naive reps 1-3 are controls for the GVHD-activated samples. Experiment Overall Design: Naive reps 4-6 are controls for the Allogeneic tumor-activated samples.

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MHC class II antigen presentation by tumoral lymphatics is required for tumor specific signature and suppressive functions of Tregs

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