Depletion of B220+NK1.1+cells enhances the rejection of established melanoma by tumor-specific CD4+T cells

Wilson, Kyle A.; Goding, Stephen R.; Neely, Harold R.; Harris, Kristina M.; Antony, Paul A.

doi:10.1080/2162402x.2015.1019196

Cited by 10 publications

(21 citation statements)

References 62 publications

(74 reference statements)

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“…Recent studies have shown that engraftment by naive CD4 + cells is enhanced in IL-15 knockout hosts [48]. Studies have also shown that deprivation of IL-15 may affect CD4 + cells indirectly through other populations [49]. Thus, our finding that absence of IL-15 has no effect on Th17 engraftment in a lymphodepleted host represents a contrast with other populations of CD4 + T cells.…”

Section: Discussionmentioning

confidence: 62%

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Neitzke

Bowers

Andrijauskaite

et al. 2017

Cancer Immunol Immunother

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Adoptive cellular therapy (ACT) with the Th17 subset of CD4+ T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that they are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets including conventionally activated CD8+ T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

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Section: Discussionmentioning

confidence: 62%

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Neitzke

Bowers

Andrijauskaite

et al. 2017

Cancer Immunol Immunother

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“…NK‐like cells are elevated in lupus‐prone mice models . One of these NK‐like cells, the recently described interferon‐producing killer dendritic cells, is reported as having a role in controlling autoimmune diseases . Our group previously found a B220 + CD38 + CD24 − CD21 − population; recent information from the literature suggested us that it may correspond to IKDC lymphocytes .…”

Section: Discussionmentioning

confidence: 73%

“…Some of these cells include the IKDCs which participate in the induction and the regulation of immunity and constitute a link between innate and adaptive immune response . These subsets play a role in tumor growth through the production of IFN‐γ . The IKDCs also possess properties of both NKs and DCs as cytotoxic functions and antigen presentation.…”

Section: Introductionmentioning

confidence: 99%

Regulatory IFN‐γ‐producing killer dendritic cells are enhanced in B6.MLR‐Fas^lpr/J lupus‐prone mice

Rodríguez-Alba

Girón-Pérez²,

Romero-Ramírez³

et al. 2018

Eur J Immunol

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A novel cell population denominated IFN-γ-producing killer dendritic cells (IKDCs) have been recently described. These cells are lymphocytes lacking B-or T-receptors, but they can be identified by the presence of B220 + CD38 + CD49b + and low CD11c, among other cell surface markers. The main characteristics of IKDCs are the production of IFN-γ and the ability to spontaneously kill tumor cells. We found that this population increases in B6.MLR-Fas lpr /J mice. Interestingly, IKDCs increase with age and are more abundant in mice older than 6 months onward. To analyze whether these cells have any role in the induction of the lupus-like phenotype in the B6.MLR-Fas lpr /J mice, IKDCs were purified and transferred into 6-month-old B6.MRL-Fas lpr /J mice, then the presence of antinuclear antibodies (ANAS) and anti-dsDNA antibodies were analyzed 2 and 4 months after the transfer. The results showed a reduction in the levels of these autoantibodies and increased survival of these mice, indicating that these cells may have a regulatory function. In vitro assays demonstrated that IKDCs reduced the proliferation of both autoreactive B and T cells, suggesting that these may be the mechanisms used by these cells to ameliorate the lupus-like phenotype in the B6.MRL-Fas lpr /J mice.Keywords: autoantibodies r autoimmune disease r autoreactive B and T cells r IFN-γ-producing killer dendritic cells (IKDCs) r systemic lupus erythematosus (SLE) Additional supporting information may be found online in the Supporting Information section at the end of the article. humans, with high prevalence among women; the incidence of this disease has increased in the last years [1]. The use of several murine models (NZB/NZW and B6.MRL-Fas lpr /J mice) allows studying the pathological processes in SLE. Those models allow to understand the cellular and genetic events that take place during the induction of autoimmunity and the defects in its regulation;

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“…injected 4T1 breast cancer is eradicated by AGM1- and NK1.1-positive cells. As only NK cells share both characteristics [58, 59] and because NK cells alone are sufficient for cure in the NK cell transfer model [1] [and this manuscript], it is apparent that the anti-tumor effect resulted from the MHC-mismatched host’s activated NK cells.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer

Gelder

Vanclée

Elssen

et al. 2016

Breast Cancer Res Treat

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PurposeAdministration of 5 million alloreactive natural killer (NK) cells after low-dose chemo-irradiation cured mice of 4T1 breast cancer, supposedly dose dependent. We now explored the efficacy of bone marrow as alternative in vivo source of NK cells for anti-breast cancer treatment, as methods for in vitro clinical scale NK cell expansion are still in developmental phases.MethodsProgression-free survival (PFS) after treatment with different doses of spleen-derived alloreactive NK cells to 4T1-bearing Balb/c mice was measured to determine a dose–response relation. The potential of bone marrow as source of alloreactive NK cells was explored using MHC-mismatched mice as recipients of 4T1. Chemo-irradiation consisted of 2× 2 Gy total body irradiation and 200 mg/kg cyclophosphamide. Antibody-mediated in vivo NK cell depletion was applied to demonstrate the NK cell’s role.ResultsAdministration of 2.5 instead of 5 million alloreactive NK cells significantly reduced PFS, evidencing dose responsiveness. Compared to MHC-matched receivers of subcutaneous 4T1, fewer MHC-mismatched mice developed tumors, which was due to NK cell alloreactivity because in vivo NK cell depletion facilitated tumor growth. Application of low-dose chemo-irradiation increased plasma levels of NK cell-activating cytokines, NK cell activity and enhanced NK cell-dependent elimination of subcutaneous tumors. Intravenously injected 4T1 was eliminated by alloreactive NK cells in MHC-mismatched recipients without the need for chemo-irradiation.ConclusionsBone marrow is a suitable source of sufficient alloreactive NK cells for the cure of 4T1 breast cancer. These results prompt clinical exploration of bone marrow transplantation from NK-alloreactive MHC-mismatched donors in patients with metastasized breast cancer.

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Depletion of B220⁺NK1.1⁺cells enhances the rejection of established melanoma by tumor-specific CD4⁺T cells

Cited by 10 publications

References 62 publications

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Regulatory IFN‐γ‐producing killer dendritic cells are enhanced in B6.MLR‐Fas^lpr/J lupus‐prone mice

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer

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Depletion of B220+NK1.1+cells enhances the rejection of established melanoma by tumor-specific CD4+T cells

Cited by 10 publications

References 62 publications

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Regulatory IFN‐γ‐producing killer dendritic cells are enhanced in B6.MLR‐Faslpr/J lupus‐prone mice

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer

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Depletion of B220⁺NK1.1⁺cells enhances the rejection of established melanoma by tumor-specific CD4⁺T cells

Regulatory IFN‐γ‐producing killer dendritic cells are enhanced in B6.MLR‐Fas^lpr/J lupus‐prone mice