CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment

Martinenaite, Evelina; Ahmad, Shamaila Munir; Hansen, Morten Bagge; Met, Özcan; Westergaard, Marie Christine Wulff; Larsen, Stine Kiaer; Klausen, Tobias Wirenfeldt; Donia, Marco; Svane, Inge Marie; Andersen, Mads Hald

doi:10.1080/2162402x.2016.1238541

Cited by 59 publications

(61 citation statements)

References 24 publications

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“…In addition to PD-L1 and IDO we and others have identified pro-inflammatory self-reactive T cells that recognized HLA-restricted epitopes derived from other proteins normally expressed by regulatory immune cells-For example, tryptophan 2,3-dioxygenase (TDO; ref. 22), C-C motif chemokine 22 (23), forkhead box P3 (Foxp3; refs. 24,25) and more recently programmed death-ligand 2 (PD-L2; ref.…”

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confidence: 99%

The Balance Players of the Adaptive Immune System

Andersen

2018

Cancer Research

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Equilibrium between immune activation and suppression may be necessary to maintain immune homeostasis, because proinflammatory effector T cells (defined as antiregulatory T cells) counteract the functions of regulatory immune cells. These self-reactive T cells recognize human leukocyte antigen (HLA)-restricted epitopes derived from proteins expressed by regulatory immune cells such as IDO, PD-L1, PD-L2, or arginase. The activation of such proinflammatory effector T cells offers a novel way to directly target the tumor microenvironment, potentially giving them considerable clinical value, especially in patients with cancer. Vaccination against genetically stable cells with regular HLA expression is an attractive way to directly target immunosuppressive cells in addition to attracting proinflammatory cells into the tumor microenvironment. Importantly, vaccination toward IDO or PD-L1 to potentiate such T cells have proven safe, with minimal toxicity in the clinical phase I trials conducted thus far..

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confidence: 99%

The Balance Players of the Adaptive Immune System

Andersen

2018

Cancer Research

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“…38 Various immune populations are trafficked to the tumor site, and Treg trafficking is mainly mediated through the production of CCL17 and CCL22 by tumor-infiltrating T cells and TAMs through the CCL17/CCL22:CCR4 axis. 21…”

Section: T Lymphocytesmentioning

confidence: 99%

“…TAMs at the PC site secrete CCL22, which is abundantly expressed in PC; this then promotes the recruitment of Tregs to the PC site, and Tregs inhibit antitumor immunity. 21 It has been demonstrated that CCR4 antagonists, a class of Treg recruitment inhibitors, block signaling through the CCL17/CCL22:CCR4 axis, prevent Treg/Th2 recruitment, and are associated with better prognosis and survival in a mouse model. 21 Although CCR8 is expressed by Th2 cells, NK cells, monocytes, and endothelial cells, it is up-regulated in TAMs and tumor-infiltrating myeloid cells; and when complexed with CCL1, it is a major source of IL-6, CCL3, CCL4, VEGF, and CXCL8.…”

Section: Tumor-associated Macrophagesmentioning

confidence: 99%

“…21 It has been demonstrated that CCR4 antagonists, a class of Treg recruitment inhibitors, block signaling through the CCL17/CCL22:CCR4 axis, prevent Treg/Th2 recruitment, and are associated with better prognosis and survival in a mouse model. 21 Although CCR8 is expressed by Th2 cells, NK cells, monocytes, and endothelial cells, it is up-regulated in TAMs and tumor-infiltrating myeloid cells; and when complexed with CCL1, it is a major source of IL-6, CCL3, CCL4, VEGF, and CXCL8. 26 The CCL1:CCR8 axis presents itself as an important pathway in cancer-associated inflammation.…”

Section: Tumor-associated Macrophagesmentioning

confidence: 99%

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Prostate Cancer

Rani

Dasgupta

Murphy

2019

The American Journal of Pathology

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Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/ detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions, and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases, along with the associated evolutionary effects that at times protect populations from one disease, could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC.

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“…PD-L1-specific and PD-L2-specific T-cell-mediated cytotoxicity was measured with conventional 51 chromium-release assays, as previously described. 15 Target cells were TAP deficient T2 cells,…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

The inhibitory checkpoint, PD-L2, is a target for effector T cells: Novel possibilities for immune therapy

et al. 2017

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Cell surface molecules of the B7/CD28 family play an important role in T-cell activation and tolerance. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied whereas PD-L2 has received less attention. However, recently the expression of PD-L2 was described to be independently associated with clinical response in anti-PD1-treated cancer patients. Here, we investigated whether PD-L2 might represent a natural target that induces specific T cells. We identified spontaneous specific T-cell reactivity against two epitopes located in the signal peptide of PD-L2 from samples from patients with cancer as well as healthy individuals ex vivo. We characterized both CD8 and CD4 PD-L2-specific T cells. Interestingly, the epitope in PD-L2 that elicited the strongest response was equivalent to a potent HLA-A2-restricted epitope in PD-L1. Importantly, PD-L1-specific and PD-L2-specific T cells did not cross-react; therefore, they represent different T-cell antigens. Moreover, PD-L2-specific T cells reacted to autologous target cells depending on PD-L2 expression. These results suggested that activating PD-L2 specific T cells (e.g., by vaccination) might be an attractive strategy for anti-cancer immunotherapy. Accordingly, PD-L2 specific T cells can directly support anti-cancer immunity by killing of target cells, as well as, indirectly, by releasing pro-inflammatory cytokines at the microenvironment in response to PD-L2-expressing immune supressive cells.

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CCL22-specific T Cells: Modulating the immunosuppressive tumor microenvironment

Cited by 59 publications

References 24 publications

The Balance Players of the Adaptive Immune System

The Balance Players of the Adaptive Immune System

Prostate Cancer

The inhibitory checkpoint, PD-L2, is a target for effector T cells: Novel possibilities for immune therapy

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