The ratio LEE011 cost of Teff cell counts versus CD11b+Gr1+ cell counts is increased about fivefold (53 ± 10, mean ± SEM) in the pancreas versus that in the tumor (9 ± 3, mean ± SEM) (Supporting Information Fig. 1). Moreover, the profile
of the populations differs in the healthy versus malignant tissues, in that the CD11b+Gr1+ cells in tumors had a much higher expression of CD11b. Treg-cell reconstitution did modestly increase circulating TGF-β1 levels in the tumor-bearing mice compared with that of control groups (Supporting information Fig. 2A). The elevated TGF-β1 level in blood circulation, however, had no apparent suppression on immunopathology in the pancreas, even though the increase in TGF-β1 was detectable before onset of immune damage in pancreas. Taken together, these results indicate that the insulinoma microenvironment, in combination with PFT�� manufacturer Treg cells and MDSC, effectively suppressed progression of autoimmunity-mediated damage of tumors by self-antigen-specific CD4+ Teff cells. This suppressive effect was local at the tumor site, with negligible systemic inhibition on the self-antigen-specific cells, as they retained their capacity in destroying nonmalignant target cells in the same animals. CD8+ T cells are potent effectors in antitumor immunity. Prompted by the observation of local suppression of autoimmune CD4+ Teff cells at the tumor site, we tested whether tumor microenvironment,
as opposed to healthy tissues, also suppress self-antigen-specific CD8+ Teff cells. The RIP-mOVA transgenic mice express an ovalbumin transgene in healthy pancreatic β cells [31]. Transgenic ovalbumin expression serves as a surrogate self antigen. These mice were used as a recipient for implanting E.G7-OVA lymphoma cells, which were stably transfected with the ovalbumin gene [32]. Adoptive transfer of activated CD8+ Teff cells from the OT1 transgenic Masitinib (AB1010) mice [33], which are specific to the ovalbumin antigen, completely destroyed the ovalbumin-expressing β cells and caused overt diabetes in the animals. However, lymphoma mass was only partially reduced, with limited inflammatory infiltration in the tumor tissue (Fig. 3).
Thus, the CD8+ Teff cells were inhibited at the tumor site in the lymphoma-bearing animals, without being substantially curtailed at the healthy tissue site expressing the same self-antigens. To further examine the pathophysiology of autoimmune mechanisms in antitumor immunity, we investigated the role of Treg cell-mediated suppression of self-antigen-specific Teff cells at tumor site in a setting that necessitated neither adoptive transfer of T cells nor lymphopenic conditions. The BDC2.5/NOD.Foxp3DTR model [34] was used. It carries a diphtheria toxin (DT) receptor transgene under the control of a Foxp3 promoter, enabling timed removal of 80–90% of Treg cells with a low dose of DT. NIT-1 tumor cells were injected into BDC2.5+ Foxp3DTR+ mice or littermate BDC2.5+Foxp3DTR− controls.