IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers

Zhang, Bin; Karrison, Theodore; Rowley, Donald A.; Schreiber, Hans

doi:10.1172/jci33522

Cited by 144 publications

(160 citation statements)

References 57 publications

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“…changes in macrophages in the tumour environment. These data are consistent with the results of Zhang et al, 46 who demonstrated that effector T cells caused tumour destruction by targeting the non-malignant cells in the tumour stroma. We show that aOX40 therapy led to a decrease in the proportion of macrophages in the tumour, and further experiments will be necessary to distinguish whether this process occurs through selective macrophage destruction by effector T cells, macrophage differentiation within the tumour, or recruitment of new macrophages to the altered tumour site.…”

Section: Discussionsupporting

confidence: 93%

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

2012

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The treatment of high-grade tumours must consider a tumour environment dominated by cells that support cancer growth. In addition to directing angiogenesis and invasion, alternatively activated macrophages in the tumour provide protection from adaptive immunity and permit tumour growth. Agonist antibodies to the tumour necrosis factor receptor family member OX40 are an effective therapy for cancer in a range of murine models; however, as with many immune therapies, aOX40 therapy is less effective as the tumour grows and develops an immune suppressive environment. We demonstrate that aOX40 directly activates T cells and that this T-cell activation alters macrophage differentiation in the tumour environment. We demonstrate that macrophages in the tumour limit the efficacy of aOX40 therapy, and that combining aOX40 therapy with inhibitors of arginase significantly enhances survival of tumour-bearing mice. These data demonstrate that macrophages in the tumour environment limit the effectiveness of OX40-based immunotherapy, and combination therapies that target both the cell-mediated immune response and the suppressive tumour environment will be required for translation of effective immunotherapies to patients with established tumours.

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Section: Discussionsupporting

confidence: 93%

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

2012

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“…It is clear from mouse models that adoptively transferred antigen-specific T cells are capable of eradicating established cancer (6)(7)(8), and the ability of CTLs to directly kill tumor and/or stromal cells is thought to be important for tumor elimination (9)(10)(11). Nonetheless, cytokines such as IFNg and TNFa produced by T cells are also likely to contribute to the prevention of tumor growth by ACT via mechanisms other than cell lysis (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

Matsushita

Hosoi

Ueha

et al. 2015

Cancer Immunology Research

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To understand global effector mechanisms of CTL therapy, we performed microarray gene expression analysis in a murine model using pmel-1 T-cell receptor (TCR) transgenic T cells as effectors and B16 melanoma cells as targets. In addition to upregulation of genes related to antigen presentation and the MHC class I pathway, and cytotoxic effector molecules, cell-cycle-promoting genes were downregulated in the tumor on days 3 and 5 after CTL transfer. To investigate the impact of CTL therapy on the cell cycle of tumor cells in situ, we generated B16 cells expressing a fluorescent ubiquitination-based cell-cycle indicator (B16-fucci) and performed CTL therapy in mice bearing B16-fucci tumors. Three days after CTL transfer, we observed diffuse infiltration of CTLs into the tumor with a large number of tumor cells arrested at the G 1 phase of the cell cycle, and the presence of spotty apoptotic or necrotic areas. Thus, tumor growth suppression was largely dependent on G 1 cell-cycle arrest rather than killing by CTLs. Neutralizing antibody to IFNg prevented both tumor growth inhibition and G 1 arrest. The mechanism of G 1 arrest involved the downregulation of S-phase kinase-associated protein 2 (Skp2) and the accumulation of its target cyclin-dependent kinase inhibitor p27 in the B16-fucci tumor cells. Because tumor-infiltrating CTLs are far fewer in number than the tumor cells, we propose that CTLs predominantly regulate tumor growth via IFNg-mediated profound cytostatic effects rather than via cytotoxicity. This dominance of G 1 arrest over other mechanisms may be widespread but not universal because IFNg sensitivity varied among tumors.

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“…29 Also, the cytokines secreted by Th1 T cells can target the tumor environment and eliminate antigen-loss tumor variants. [30][31][32] Finally, tumor antigen-specific Th1 T cells can also directly target tumor cells through cytotoxicity, FASL, or senescence induction. [33][34][35][36] Therefore, the percentage of Th1 CD4 C T cells in the stromal environment is directly correlated with a cancer patient's prognosis.…”

Section: E1232220-12mentioning

confidence: 99%

Targeting B-cell malignancies through human B-cell receptor specific CD4⁺T cells

Weng¹,

Baio²,

Moriarty³

et al. 2016

OncoImmunology

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The B-cell receptor (BCR) expressed by a clonal B cell tumor is a tumor specific antigen (idiotype). However, the T-cell epitopes within human BCRs which stimulate protective immunity still lack detailed characterization. In this study, we identified 17 BCR peptide-specific CD4 C T-cell epitopes derived from BCR heavy and light chain variable region sequences. Detailed analysis revealed these CD4 C T-cell epitopes stimulated normal donors' and patients' Th1 CD4C T cells to directly recognize the autologous tumors by secretion of IFNg, indicating the epitopes are processed and presented by tumor cells. One BCR peptide-specific CD4 C T cell line was also cytotoxic and lysed autologous tumor cells through the perforin pathway. Sequence analysis of the epitopes revealed that 10 were shared by multiple primary patients' tumors, and 16 had the capacity to bind to more than one HLA DRB1 allele. T cells stimulated by shared epitopes recognized primary tumors expressing the same sequences on multiple HLA DRB1 alleles. In conclusion, we identified 17 BCR-derived CD4C T-cell epitopes with promiscuous HLA DRB1 binding affinity that are shared by up to 36% of patients, suggesting a strategy to overcome the requirement for individual preparation of therapeutic agents targeting idiotype.

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IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers

Cited by 144 publications

References 57 publications

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

Targeting B-cell malignancies through human B-cell receptor specific CD4⁺T cells

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IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers

Cited by 144 publications

References 57 publications

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

Targeting macrophages in the tumour environment to enhance the efficacy of αOX40 therapy

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

Targeting B-cell malignancies through human B-cell receptor specific CD4+T cells

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Product

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Targeting B-cell malignancies through human B-cell receptor specific CD4⁺T cells