Complement C5a Receptor Facilitates Cancer Metastasis by Altering T-Cell Responses in the Metastatic Niche

Vadrevu, Saurya Kumari; Chintala, Navin K.; Sharma, Sharad; Sharma, Priya; Cleveland, Clayton; Riediger, Linley; Manne, Sasikanth; Fairlie, David P.; Gorczyca, Wojciech; Almanza, Othon; Karbowniczek, Magdalena; Markiewski, Maciej M.

doi:10.1158/0008-5472.can-14-0157

Cited by 152 publications

(205 citation statements)

References 46 publications

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“…To determine the time interval in which premetastatic changes occur, we tracked 4T1 cells that expressed GFP (4T1-GFP + ) and determined that tumor cells arrived to the lungs at day 20, at the earliest, as a result of spontaneous metastasis of the implanted breast tumors (12). Therefore, we concluded that the accumulation of AM and other immune cells observed in this model, using the same 4T1 clone ( Fig.…”

Section: Resultsmentioning

confidence: 86%

“…As negative controls, unstimulated cells were used. Cytokine production was assessed by standard intracellular cytokine staining procedure, as described in our earlier study (12). Staining for Ki-67 was performed after permeabilization with 70% chilled ethanol.…”

Section: Cell Isolation Stimulation and Facsmentioning

confidence: 99%

“…Analysis was performed using ImageScope (Aperio). Quantitative real-time PCR for C5 was performed as described by us earlier (12). C5 (forward: 59-CCTGTTACCAGTGATGAAGGCAG-39; reverse: 59-TCG-TTAGTGAGTCAGGCAGCGT-39) primers were procured from SigmaAldrich (St. Louis, MO).…”

Section: Immunofluorescence Immunohistochemistry and Quantitative Pcrmentioning

confidence: 99%

“…Thus, the intrinsic properties of lung immune homeostasis could be, at least partially, responsible for the susceptibility of the lungs to metastasis. Complement plays an important part in regulating macrophage function and migration during the inflammatory reaction (11), and we have demonstrated activation of complement in the lung premetastatic niche (12); therefore, we also determined the impact of complement C5a receptor (C5aR) on AM accumulation in the premetastatic niche.…”

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confidence: 99%

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Pulmonary Alveolar Macrophages Contribute to the Premetastatic Niche by Suppressing Antitumor T Cell Responses in the Lungs

Sharma

Chintala

Vadrevu

et al. 2015

The Journal of Immunology

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In contrast to tumor-associated macrophages, myeloid-derived suppressor cells, or inflammatory monocytes, functions of tissue resident macrophages, including alveolar macrophages (AM), in cancer were not well studied. Using a mouse model of breast cancer, we show that AM promote cancer metastasis to the lungs by suppressing antitumor T cells in this organ. AM accumulated in the premetastatic lungs through complement C5a receptor–mediated proliferation but not through recruitment from the circulation. AM preconditioned by breast tumors inhibited Th1 and favored generation of Th2 cells that had lower tumoricidal activity than Th1 cells. In addition, AM reduced the number and maturation of lung dendritic cells by regulating TGF-β in the lung environment. Depletion of AM reversed immunosuppression imposed by these cells and strengthened local Th1 responses, which significantly reduced lung metastatic burden. C5a receptor deficiency, which also lessens myeloid-derived suppressor cells in the premetastatic niche, synergized with the depletion of AM in preventing metastasis, leading to protection of mice from lung metastases. This study identifies AM as a new component of the premetastatic niche, which is harnessed by tumors to impose immunosuppression, and as a new target for cancer immunotherapies to eliminate or reduce metastasis. Because the lungs are the most common target for hematogenous metastasis, this research offers a plausible explanation for susceptibility of the lungs to cancer metastasis.

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Section: Resultsmentioning

confidence: 86%

Section: Cell Isolation Stimulation and Facsmentioning

confidence: 99%

Section: Immunofluorescence Immunohistochemistry and Quantitative Pcrmentioning

confidence: 99%

mentioning

confidence: 99%

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Pulmonary Alveolar Macrophages Contribute to the Premetastatic Niche by Suppressing Antitumor T Cell Responses in the Lungs

Sharma

Chintala

Vadrevu

et al. 2015

The Journal of Immunology

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133

124

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“…The role of C5aR on MDSC modulation was also confirmed in the model Lewis lung carcinoma (3LL) (65). In addition, in a mouse model of breast cancer, C5aR was shown to promote metastasis by suppressing CD8 + T cell function and by enhancing Treg generation (66). In the same model, alveolar macrophages were shown to contribute to the metastatic potential in a C5aR dependent manner (67).…”

Section: Modulation Of Infiltration and Activation Of Immune Cells Bymentioning

confidence: 83%

The dual role of complement in cancer and its implication in anti-tumor therapy

Kourtzelis¹,

Rafail

2016

Ann. Transl. Med.

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Impaired T cell function in malignant pleural effusion is caused by TGF‐β derived predominantly from macrophages

Wang

et al. 2016

Intl Journal of Cancer

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Malignant pleural effusion (MPE) is an indication of advanced cancer. Immune dysfunction often occurs in MPE. We aimed to identify the reason for impaired T cell activity in MPE from lung cancer patients and to provide clues toward potential immune therapies for MPE. The surface inhibitory molecules and cytotoxic activity of T cells in MPE and peripheral blood (PB) were analyzed using flow cytometry. Levels of inflammatory cytokines in MPE and PB were tested using ELISA. TGF-β expression in tumor-associated macrophages (TAMs) was also analyzed. The effect of TAMs on T cells was verified in vitro. Lastly, changes in T cells were evaluated following treatment with anti-TGF-β antibody. We found that expression levels of Tim-3, PD-1 and CTLA-4 in T cells from MPE were upregulated compared with those from PB, but levels of IFN-γ and Granzyme B were downregulated (p < 0.05). The amount of TGF-β was significantly higher in MPE than in PB (p < 0.05). TGF-β was mainly produced by TAMs in MPE. When T cells were co-cultured with TAMs, expression levels of Tim-3, PD-1 and CTLA-4 were significantly higher than controls, whereas levels of IFN-γ and Granzyme B were significantly decreased, in a dose-dependent manner (p < 0.05). In vitro treatment with anti-TGF-β antibody restored the impaired T cell cytotoxic activity in MPE. Our results indicate that macrophage-derived TGF-β plays an important role in impaired T cell cytotoxicity. It will therefore be valuable to develop therapeutic strategies against TGF-β pathway for MPE therapy of lung cancer.

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Complement C5a Receptor Facilitates Cancer Metastasis by Altering T-Cell Responses in the Metastatic Niche

Abstract: The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR)

Cited by 152 publications

References 46 publications

Pulmonary Alveolar Macrophages Contribute to the Premetastatic Niche by Suppressing Antitumor T Cell Responses in the Lungs

Pulmonary Alveolar Macrophages Contribute to the Premetastatic Niche by Suppressing Antitumor T Cell Responses in the Lungs

The dual role of complement in cancer and its implication in anti-tumor therapy

Impaired T cell function in malignant pleural effusion is caused by TGF‐β derived predominantly from macrophages

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