Primary 4T1 tumor resection provides critical “window of opportunity” for immunotherapy

Ghochikyan, Anahit; Davtyan, Arpine; Hovakimyan, Armine; Poghosyan, Anna; Bagaev, Alexander; Ataullakhanov, Ravshan; Nelson, Edward L.; Agadjanyan, Michael G.

doi:10.1007/s10585-013-9619-0

Cited by 25 publications

(24 citation statements)

References 41 publications

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“…3B and C), but this population expanded with progressive tumor growth. Consistent with previous reports, [47][48][49] the CD11b C Gr-1 C population declined following tumor resection. However, the CD11b C Gr-1 C population later surged as metastatic lesions developed in the mice receiving no additional treatment (data not shown), mice treated with unloaded DCs, and a subset of mice that relapsed following NKT cell activation therapy (Fig.…”

Section: Glycolipid Treatments Reduce Metastasissupporting

confidence: 92%

“…Given that the primary tumor is responsible for the initial elevation in MDSC levels, 47 it was not clear whether the sustained reduction in circulating MDSCs following NKT cell activation was due to direct effects of NKT cells on MDSCs or due to maintenance of a reduced tumor burden. To determine whether NKT cells directly altered levels of circulating MDSCs, we activated NKT cells in unresected mice (day 7 post-tumor inoculation).…”

Section: Glycolipid Treatments Reduce Metastasismentioning

confidence: 99%

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Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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Metastatic lesions are responsible for over 90% of breast cancer associated deaths. Therefore, strategies that target metastasis are of particular interest. This study examined the efficacy of natural killer T (NKT) cell activation as a postsurgical immunotherapy in a mouse model of metastatic breast cancer. Following surgical resection of orthotopic 4T1 mammary carcinoma tumors, BALB/c mice were treated with NKT cell activating glycolipid antigens (a-GalCer, a-CGalCer or OCH) or a-GalCer-loaded dendritic cells (DCs). Low doses of glycolipids transiently reduced metastasis but did not increase survival. A high dose of a-GalCer enhanced overall survival, but was associated with increased toxicity and mortality at early time points. Treatment with a-GalCer-loaded DCs limited tumor metastasis, prolonged survival, and provided curative outcomes in »45% of mice. However, survival was not increased further by additional DC treatments or co-transfer of expanded NKT cells. NKT cell activation via glycolipid-loaded DCs decreased the frequency and immunosuppressive activity of myeloid derived suppressor cells (MDSCs) in tumor-resected mice. In vitro, NKT cells were resistant to the immunosuppressive effects of MDSCs and were able to reverse the inhibitory effects of MDSCs on T cell proliferation. NKT cell activation enhanced antitumor immunity in tumor-resected mice, increasing 4T1-specific cytotoxic responses and IFNg production from natural killer (NK) cells and CD8 C T cells. Consistent with increased tumor immunity, mice surviving to day 150 were resistant to a second tumor challenge. This work provides a clear rationale for manipulating NKT cells to target metastatic disease.

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Section: Glycolipid Treatments Reduce Metastasissupporting

confidence: 92%

Section: Glycolipid Treatments Reduce Metastasismentioning

confidence: 99%

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

et al. 2015

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“…While the presence of CD11b + Gr1 + cells in the lungs has been associated with enhanced growth of metastatic tumor cell foci [17][18][19], CD11b + Gr1 + cells have also been shown to accumulate in non-metastatic target organs of tumor-bearing mice [27] and in the peripheral blood of breast cancer patients [28][29][30]. Primary tumor resection in mice is known to decrease MDSC levels in the spleen [31,32], although the longevity of MDSCs in the lungs after primary tumor resection, and the potential impact of these MDSCs on metastatic growth in the lungs, is less well-understood.…”

Section: Introductionmentioning

confidence: 99%

Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs

Bosiljcic

Cederberg

Hamilton³

et al. 2019

Breast Cancer Res

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Background: Solid tumors produce proteins that can induce the accumulation of bone marrow-derived cells in various tissues, and these cells can enhance metastatic tumor growth by several mechanisms. 4T1 murine mammary tumors are known to produce granulocyte colony-stimulating factor (G-CSF) and increase the numbers of immunosuppressive CD11b + Gr1 + myeloid-derived suppressor cells (MDSCs) in tissues such as the spleen and lungs of tumor-bearing mice. While surgical resection of primary tumors decreases MDSC levels in the spleen, the longevity and impact of MDSCs and other immune cells in the lungs after tumor resection have been less studied. Methods: We used mass cytometry time of flight (CyTOF) and flow cytometry to quantify MDSCs in the spleen, peripheral blood, and lungs of mice bearing orthotopic murine mammary tumors. We also tested the effect of primary tumor resection and/or gemcitabine treatment on the levels of MDSCs, other immune suppressor and effector cells, and metastatic tumor cells in the lungs. Results: We have found that, similar to mice with 4T1 tumors, mice bearing metastatic 4T07 tumors also exhibit accumulation of CD11b + Gr1 + MDSCs in the spleen and lungs, while tissues of mice with non-metastatic 67NR tumors do not contain MDSCs. Mice with orthotopically implanted 4T1 tumors have increased granulocytic (G-) MDSCs, monocytic (M-) MDSCs, macrophages, eosinophils, and NK cells in the lungs. Resection of primary 4T1 tumors decreases G-MDSCs, M-MDSCs, and macrophages in the lungs within 48 h, but significant numbers of functional immunosuppressive G-MDSCs persist in the lungs for 2 weeks after tumor resection, indicative of an environment that can promote metastatic tumor growth. The chemotherapeutic agent gemcitabine depletes G-MDSCs, M-MDSCs, macrophages, and eosinophils in the lungs of 4T1 tumor-bearing mice, and we found that treating mice with gemcitabine after primary tumor resection decreases residual G-MDSCs in the lungs and decreases subsequent metastatic growth.

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“…injected MHC-mismatched hematopoietic stem cells are rejected by host NK cells even in lethally irradiated mice (the so-called “hybrid resistance model” [66]). Another effect may be a reduction of 4T1 tumor-induced NK cell inhibitory elements like regulatory T cells and myeloid-derived suppressor cells [63, 67–73], similar to its relevance for disease-specific T-cell therapy [74]. …”

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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Primary 4T1 tumor resection provides critical “window of opportunity” for immunotherapy

Cited by 25 publications

References 41 publications

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs

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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