Purpose The goals of the study were to elucidate the immune mechanisms that contribute to desirable complete remissions of murine colon tumors treated with single radiation dose of 30 Gy. This dose is at the upper end of the ablative range used clinically to treat advanced or metastatic colorectal, liver, and non-small cell lung tumors. Experimental design Changes in the tumor immune microenvironment of single tumor nodules exposed to radiation were studied using 21 day (>1 cm in diameter) CT26 and MC38 colon tumors. These are well-characterized weakly immunogenic tumors. Results We found that the high dose radiation transformed the immunosuppressive tumor microenvironment resulting in an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells (MDSCs). The change was dependent on antigen cross-presenting CD8+ dendritic cells, secretion of IFN-γ, and CD4+ T cells expressing CD40L. Anti-tumor CD8+ T cells entered tumors shortly after radiotherapy, reversed MDSC infiltration, and mediated durable remissions in an IFN-γ dependent manner. Interestingly, extended fractionated radiation regimen did not result in robust CD8+ T cell infiltration. Conclusion For immunologically sensitive tumors, these results indicate that remissions induced by a short course of high dose radiation therapy depend on the development of anti-tumor immunity that is reflected by the nature and kinetics of changes induced in the tumor cell microenvironment. These results suggest that systematic examination of the tumor immune microenvironment may help in optimizing the radiation regimen used to treat tumors by adding a robust immune response.
IntroductionCD4 ϩ CD25 ϩ regulatory T (Treg) cells are potent modulators of immune responses. We and others have demonstrated that donorderived CD4 ϩ CD25 ϩ Treg cells could suppress lethal acute graft-versus-host disease (aGVHD) in murine models of allogeneic bone marrow transplantation. [1][2][3] In these models, cotransplantation of Treg cells with conventional donor T cells controlled the expansion of alloaggressive T cells in recipient animals, thereby interfering with one of the major events in the initiation phase of aGVHD. 4 Importantly, donor Treg cells did not cause generalized immune paralysis, since the beneficial graft-versus-leukemia/ lymphoma (GVL) effect of donor T cells was maintained. [4][5][6] Modulating alloimmune responses after bone marrow or hematopoietic stem cell transplantation with adoptively transferred donor CD4 ϩ CD25 ϩ Treg cells thus appears as a promising strategy for the prevention or therapy of aGVHD in humans.CD62L (L-selectin) is an important T-cell homing receptor as well as a marker for T-cell development. Naive T cells are CD62L ϩ and interaction of CD62L with its ligands, a group of molecules collectively referred to as peripheral node addressin (PNAd), is crucial for T-cell entry into lymph nodes (LNs) via high endothelial venules. 7 Expression of CD62L is rapidly lost following T-cell receptor engagement, and CD62L Ϫ T cells are thought to be "antigen experienced." There are 2 recent publications demonstrating that CD62L Ϫ donor T cells did not cause GVHD. 8,9 While CD4 ϩ CD62L Ϫ T cells contained a higher fraction of CD4 ϩ CD25 ϩ Treg cells, their inability to induce GVHD was maintained after Treg cell depletion. 8 Nevertheless, these findings called for the reciprocal analysis of the GVHD-regulating capacity of CD62L ϩ and CD62L Ϫ subsets of CD4 ϩ CD25 ϩ Treg cells.Comparing the effects CD4 ϩ CD25 ϩ CD62L ϩ and CD62L Ϫ Treg cell subpopulations in aGVHD was suggested by a second line of investigations. Both subsets had been shown to be equally anergic and suppressive upon polyclonal stimulation in vitro. [10][11][12] Interestingly, we found that in an adoptive transfer model of diabetes into nonobese diabetic-severe combined immunodeficient (NOD-scid) mice, only the CD62L ϩ but not the CD62L Ϫ subset of CD4 ϩ CD25 ϩ Treg cells caused a significant delay of disease onset. 12 In contrast, another group reported recently that both CD62L ϩ and CD62L Ϫ Treg cell subsets were protective in an adoptive transfer model of colitis, 13 suggesting that the inconsistency between in vitro and in vivo experiments in NOD mice may have been related to peculiarities of this mouse strain, which spontaneously develops autoimmune diabetes. In the current study, we used the aGVHD model as an additional in vivo assay for suppressor function in a nonautoimmune disease-prone strain.Using a mouse model for lethal aGVHD induced by major histocompatibility complex (MHC)-mismatched CD4 ϩ CD25 Ϫ T cells, 1 we found that only the CD62L ϩ subpopulation of CD4 ϩ CD25 ϩ T cells protected recipients aga...
Allogeneic bone marrow transplantation is a curative treatment for leukemia and lymphoma, but graft-vs-host disease (GVHD) remains a major complication. Using a GVHD protective nonmyeloablative conditioning regimen of total lymphoid irradiation and antithymocyte serum (TLI/ATS) in mice that has been recently adapted to clinical studies, we show that regulatory host NKT cells prevent the expansion and tissue inflammation induced by donor T cells, but allow retention of the killing activity of donor T cells against the BCL1 B cell lymphoma. Whereas wild-type hosts given transplants from wild-type donors were protected against progressive tumor growth and lethal GVHD, NKT cell-deficient CD1d−/− and Jα-18−/− host mice given wild-type transplants cleared the tumor cells but died of GVHD. In contrast, wild-type hosts given transplants from CD8−/− or perforin−/− donors had progressive tumor growth without GVHD. Injection of host-type NKT cells into Jα-18−/− host mice conditioned with TLI/ATS markedly reduced the early expansion and colon injury induced by donor T cells. In conclusion, after TLI/ATS host conditioning and allogeneic bone marrow transplantation, host NKT cells can separate the proinflammatory and tumor cytolytic functions of donor T cells.
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