Tumors Escape CD4+ T-cell–Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens

Tveita, Anders Aune; Schjesvold, Fredrik; Haabeth, Ole Audun Werner; Fauskanger, Marte; Bogen, Bjarne

doi:10.1158/0008-5472.can-14-3640

Cited by 25 publications

(19 citation statements)

References 43 publications

(56 reference statements)

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“…While previous reports suggest modest secretion of complete Ig in B-cell malignancies including chronic lymphocytic leukemia and non-Hodgkin's lymphoma (34,35), other studies indicate that a significant release of free Ig L chain may occur in such patients (36,37). The latter observation is noteworthy, given recent data from our group showing that uptake and presentation of free L chains by tumor-infiltrating macrophages is approximately 100-fold more efficient compared with complete Ig (20,38).…”

Section: Discussionmentioning

confidence: 81%

CD4+ T-cell–Mediated Rejection of MHC Class II–Positive Tumor Cells Is Dependent on Antigen Secretion and Indirect Presentation on Host APCs

et al. 2018

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Tumor-specific CD4 T cells have been shown to mediate efficient antitumor immune responses against cancer. Such responses can occur through direct binding to MHC class II (MHC II)-expressing tumor cells, or indirectly via activation of professional antigen-presenting cells (APC) that take up and present the tumor antigen. We have previously shown that CD4 T cells reactive against an epitope within the Ig light chain variable region of a murine B-cell lymphoma can reject established tumors. Given the presence of MHC II molecules at the surface of lymphoma cells, we investigated whether MHC II-restricted antigen presentation on tumor cells alone was required for rejection. Variants of the A20 B lymphoma cell line that either secreted or intracellularly retained different versions of the tumor-specific antigen revealed that antigen secretion by the MHC II-expressing tumor cells was essential both for the priming and effector phase of CD4 T-cell-driven antitumor immune responses. Consistent with this, genetic ablation of MHC II in tumor cells, both in the case of B lymphoma and B16 melanoma, did not preclude rejection of tumors by tumor antigen-specific CD4 T cells These findings demonstrate that MHC class II expression on tumor cells themselves is not required for CD4 T-cell-mediated rejection and that indirect display on host APC is sufficient for effective tumor elimination. These results support the importance of tumor-infiltrating APC as mediators of tumor cell killing by CD4 T cells. Elimination of tumors by CD4 T cells recognizing secreted tumor neoantigens can occur in the absence of tumor cell-intrinsic MHC II expression, highlighting the potential clinical relevance of indirect antigen recognition by tumor-infiltrating APC. http://cancerres.aacrjournals.org/content/canres/78/16/4573/F1.large.jpg .

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Section: Discussionmentioning

confidence: 81%

CD4+ T-cell–Mediated Rejection of MHC Class II–Positive Tumor Cells Is Dependent on Antigen Secretion and Indirect Presentation on Host APCs

et al. 2018

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“…There have been many obstacles for the development of immunotherapies, including the ability of tumors to adapt to immune attack, known as immunoeditting, and the immunosuppressive environment supported by TAMs and other stromal cells (48, 49). Further, the development of TAM targeting therapies has been complicated by the diversity of TAM phenotypes within tumors (3, 49, 50).…”

Section: Discussionmentioning

confidence: 99%

Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages

Iwanowycz

Wang

Hodge

et al. 2016

Molecular Cancer Therapeutics

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Macrophage infiltration correlates with severity in many types of cancer. Tumor cells recruit macrophages and educate them to adopt an M2-like phenotype through the secretion of chemokines and growth factors, such as MCP1 and CSF1. Macrophages in turn promote tumor growth through supporting angiogenesis, suppressing anti-tumor immunity, modulating extracellular matrix remodeling, and promoting tumor cell migration. Thus tumor cells and macrophages interact to create a feedforward loop supporting tumor growth and metastasis. In this study, we tested the ability of emodin, a Chinese herb-derived compound, to inhibit breast cancer growth in mice and examined the underlying mechanisms. Emodin was used to treat mice bearing EO771 or 4T1 breast tumors. It was shown that emodin attenuated tumor growth by inhibiting macrophage infiltration and M2-like polarization, accompanied by increased T cell activation and reduced angiogenesis in tumors. The tumor inhibitory effects of emodin were lost in tumor-bearing mice with macrophage depletion. Emodin inhibited IRF4, STAT6, and C/EBPβ signaling and increased inhibitory histone H3 lysine 27 tri-methylation (H3K27m3) on the promoters of M2 related genes in tumor-associated macrophages. In addition, emodin inhibited tumor cell secretion of MCP1and CSF1, as well as expression of surface anchoring molecule Thy-1, thus suppressing macrophage migration towards and adhesion to tumor cells. These results suggest that emodin acts on both breast cancer cells and macrophages and effectively blocks the tumor-promoting feedforward loop between the two cell types, thereby inhibiting breast cancer growth and metastasis.

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“…This strongly suggests that during the processing of IgGs in the endolysosome, Tregitope peptides 167 and 289 are either not efficiently generated or too readily degraded. On one side, relative resistance of Ig to processing has been demonstrated in a mouse tumor model showing that free light chains were much more efficient than complete Ig molecules in stimulating idiotype-specific T cells [30], which is in line with similar findings for ''preprocessed'' Ig fragments [31]. On the other side, the concept of rapid degradation is supported by the finding that after loading of DCs with the ''naked'' peptides 167 and 289, both peptides were degraded as indicated by the detection of several shorter length variants, while peptide 289 was more heavily degraded than peptide 167.…”

Section: Discussionmentioning

confidence: 99%

Tregitopes and impaired antigen presentation: Drivers of the immunomodulatory effects of IVIg?

Sordé

Spindeldreher

Palmer

et al. 2017

Immunity Inflam & Disease

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IntroductionAlthough intravenous immunoglobulin (IVIg) is commonly used in the clinic to treat various autoimmune and severe inflammatory diseases, the mode of action is not fully elucidated. This work investigates two proposed mechanisms: (1) the potential role of regulatory T‐cell epitopes (Tregitopes) from the constant domain of IgG in the immunosuppressive function of IVIg; and (2) a potential impact of IVIg on the ability of antigen presenting cells (APCs) to present peptides.Methods and ResultsInvestigation of the HLA class II peptide repertoire from IVIg‐loaded dendritic cells (DCs) via MHC‐associated peptide proteomics (MAPPs) revealed that numerous IgG‐derived peptides were strongly presented along the antibody sequence. Surprisingly, Tregitopes 167 and 289 did not show efficient natural presentation although they both bound to HLA class II when directly loaded as “naked” peptides on human DCs. In addition, both Tregitopes could not reproduce the inhibitory effect of IVIg in a human in vitro T‐cell proliferation assay as well as in vivo in mice. MAPPs data demonstrate that presentation of peptides from several antigens remained unchanged even when competed with high doses of IVIg, in both human and mouse.ConclusionThese data suggest that the effects mediated by IVIg are not caused by Tregitopes nor by impaired antigen presentation.

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Tumors Escape CD4+ T-cell–Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens

Cited by 25 publications

References 43 publications

CD4+ T-cell–Mediated Rejection of MHC Class II–Positive Tumor Cells Is Dependent on Antigen Secretion and Indirect Presentation on Host APCs

CD4+ T-cell–Mediated Rejection of MHC Class II–Positive Tumor Cells Is Dependent on Antigen Secretion and Indirect Presentation on Host APCs

Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages

Tregitopes and impaired antigen presentation: Drivers of the immunomodulatory effects of IVIg?

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