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 159 publications

(210 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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146

135

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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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The complement system as a target in cancer immunotherapy

Merle,

Roumenina

2024

Eur J Immunol

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Malignant cells are part of a complex network within the tumor microenvironment, where their interaction with host cells and soluble mediators, including complement components, is pivotal. The complement system, known for its role in immune defense and homeostasis, exhibits a dual effect on cancer progression. This dichotomy arises from its antitumoral opsonophagocytosis and cytotoxicity versus its protumoral chronic inflammation mediated by the C5a/C5aR1 axis, influencing antitumor T‐cell responses. Recent studies have revealed distinct co‐expression patterns of complement genes in various cancer types, correlating with prognosis. Notably, some cancers exhibit co‐regulated overexpression of complement genes associated with poor prognosis, while others show favorable outcomes. However, significant intra‐patient heterogeneity further complicates this classification. Moreover, the involvement of locally produced and intracellular complement proteins adds complexity to the tumor microenvironment dynamics. This review highlights the unique interplay of complement components within different cancers and patient cohorts, showing that “one size does not fit all”, for complement in cancer. It summarizes the clinical trials for complement targeting in cancer, emphasizing the need for tailored therapeutic approaches. By elucidating the mechanistic basis of complement's context‐dependent role, this review aims to facilitate the development of personalized cancer therapies, ultimately improving patient care and outcomes.

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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 159 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

The complement system as a target in cancer immunotherapy

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