CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function

The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients.

Section: Chemokine Signals Enabling Immune Evasioncontrasting

confidence: 88%

Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician

Adams

Moser

Karagiannis

et al. 2021

“…Preclinical studies in mice modelling colon (BC38, CT26), melanoma (B16F10), breast (EMT6) and urothelial (MB49) cancer revealed that tumor Treg cells expressed high levels of CCR8 whose targeting in monotherapies with mouse CCR8-specific antibodies resulted in significant inhibition of tumor growth, equivalent to what has been seen with anti-PD-1 blocking antibodies [55][56][57][58][59]. The primary mode of action was reported to involve antibody-dependent cellular cytotoxicity (ADCC) leading to the elimination of CCR8-expressing tumor Treg cells [56,58]. Combination therapies using antibodies specific for both CCR8 and PD-1 led to near complete arrest in tumor progression, indicating that these reagents work in synergy.…”

Section: Ccr8 Marks Activated Intratumoral Treg Cellsmentioning

confidence: 86%

“…As suggested by the recent data from several mouse cancer models [55][56][57][58][59], CCR8 represents a promising target for cancer immunotherapy. Following the lead of mogamulizumab, ADCC-active antibodies to CCR8 could bind to and eliminate tumor-associated Treg cells, notably the most activated and suppressive fraction of Treg cells that selectively express this chemokine receptor.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, two reports described the selective expression of the chemokine receptor CCR8 on tumor-associated Treg cells recovered from patients with breast cancer (BC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and melanoma (ME) [49,50]. Subsequent global gene and protein expression studies confirmed and extended these findings to additional solid tumors, both in humans [51][52][53][54] and in mice [55][56][57][58][59]. The discussions in the following chapters are focused on the chemokine receptor CCR8 and the prospect for success of CCR8-targeted therapies in patients with solid cancer.…”

Section: Treg Cell-targeted Therapiesmentioning

confidence: 95%

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Chemokine Receptor-Targeted Therapies: Special Case for CCR8

Moser

2022

Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Recent reports revealed the selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. In this review, I summarize our current knowledge about the cellular distribution and function of CCR8 in physiological and pathophysiological processes. The discussion includes an assessment of how the removal of CCR8-expressing cells might affect both anti-tumor immunity as well as immune homeostasis at remote sites. Based on these considerations, CCR8 appears to be a promising novel target to be considered in future translational research.

“…CCR8 is also expressed by Treg cells and its expression is relatively selective for Treg cells and minimal in other immune cells [ 183 , 184 ]. CCR8-expressing Treg cells are also considered to have augmented suppressor activity [ 185 , 223 ]. Indeed, CCR8 has been shown to play a pivotal role in tumor progression by regulating the localization and function of Treg cells in murine cancer models [ 185 ].…”

Section: The Chemokine Superfamily As Therapeutic Targets In Cancer Immunotherapymentioning

confidence: 99%

Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity

Matsuo

Yoshie

Nakayama

2021

Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.