Role of Chemokines and Chemokine Receptors in Shaping the Effector Phase of the Antitumor Immune Response (original) (raw)
Related papers
Chemokine-chemokine receptors in cancer immunotherapy
Immunotherapy, 2009
A surge in interest in the chemokine-chemokine receptor network is probably related to the expanding roles that chemokines have now been identified to play in human biology, particularly immunity. Specific tissue microenvironments express distinct chemokines and both hematopoietic and nonhematopoietic cells have receptor expression profiles that permit the coordinated trafficking and organization of cells within these specific tissues. Since the chemokine network plays critical roles in both the function of the immune system and the progression of cancer, it is an attractive target for therapeutic manipulation. This review will focus on chemokine and chemokine receptor network-related therapeutic interventions that utilize host-tumor interactions particularly involving the immune system.
Mediators of inflammation, 2014
Chemokines were initially identified as bioactive substances, which control the trafficking of inflammatory cells including granulocytes and monocytes/macrophages. Moreover, chemokines have profound impacts on other types of cells associated with inflammatory responses, such as endothelial cells and fibroblasts. These observations would implicate chemokines as master regulators in various inflammatory responses. Subsequent studies have further revealed that chemokines can regulate the movement of a wide variety of immune cells including lymphocytes, natural killer cells, and dendritic cells in both physiological and pathological conditions. These features endow chemokines with crucial roles in immune responses. Furthermore, increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of cancer cells. It is widely acknowledged that cancer develops and progresses to invade and metastasize in continuous interaction with noncancerous...
Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells
The Journal of experimental medicine, 2011
Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy.
Manipulating the chemokine-chemokine receptor network to treat cancer
Cancer, 2007
Chemokines are chemoattractant cytokines that regulate the trafficking and activation of leukocytes and other cell types under a variety of inflammatory and noninflammatory conditions. Over the past few years, studies have increasingly shown that chemokines play an important role in several aspects of tumor progression. Tumor cells express functional chemokine receptors, which can sustain proliferation, angiogenesis, and survival and promote organ-specific localization of distant metastases. Chemokine expression in human malignancies is associated with a leukocyte infiltration favoring the establishment of immune escape mechanisms. A literature review of relevant publications on preclinical testing of cancer therapies based on interference with the cancer chemokine network was performed. The feasibility, potential advantages, and limitations of the clinical translation of the results of such studies in treatment of different tumor types and settings are discussed. The chemokine network is a key player in the establishment of metastases. In the preclinical setting, blocking agents and antibodies directed against CXCR4 prevent metastasis of different cancers. In mouse models, overexpression of selected chemokines causes tumor infiltration by distinct leukocyte subsets, resulting in tumor regression and tumor-specific immunity generation. Researchers have also successfully used chemokines as carriers and/or adjuvants for cancer vaccines. The cancer chemokine network is a multifaceted therapeutic target.
Beyond Cell Motility: The Expanding Roles of Chemokines and Their Receptors in Malignancy
Frontiers in Immunology, 2020
The anti-tumor activities of some members of the chemokine family are often overcome by the functions of many chemokines that are strongly and causatively linked with increased tumor progression. Being key leukocyte attractants, chemokines promote the presence of inflammatory pro-tumor myeloid cells and immune-suppressive cells in tumors and metastases. In parallel, chemokines elevate additional pro-cancerous processes that depend on cell motility: endothelial cell migration (angiogenesis), recruitment of mesenchymal stem cells (MSCs) and site-specific metastasis. However, the array of chemokine activities in cancer expands beyond such "typical" migration-related processes and includes chemokine-induced/mediated atypical functions that do not activate directly motility processes; these non-conventional chemokine functions provide the tumor cells with new sets of detrimental tools. Within this scope, this review article addresses the roles of chemokines and their receptors at atypical levels that are exerted on the cancer cell themselves: promoting tumor cell proliferation and survival; controlling tumor cell senescence; enriching tumors with cancer stem cells; inducing metastasis-related functions such as epithelial-to-mesenchymal transition (EMT) and elevated expression of matrix metalloproteinases (MMPs); and promoting resistance to chemotherapy and to endocrine therapy. The review also describes atypical effects of chemokines at the tumor microenvironment: their ability to up-regulate/stabilize the expression of inhibitory immune checkpoints and to reduce the efficacy of their blockade; to induce bone remodeling and elevate osteoclastogenesis/bone resorption; and to mediate tumor-stromal interactions that promote cancer progression. To illustrate this expanding array of atypical chemokine activities at the cancer setting, the review focuses on major metastasis-promoting inflammatory chemokines-including CXCL8 (IL-8), CCL2 (MCP-1), and CCL5 (RANTES)-and their receptors. In addition, non-conventional activities of CXCL12 which is a key regulator of tumor progression, and its CXCR4 receptor are described, alongside with the other CXCL12-binding receptor CXCR7 (RDC1). CXCR7, a member of the subgroup of atypical chemokine receptors (ACKRs) known also as ACKR3, opens the gate for discussion of atypical activities of additional ACKRs in cancer: ACKR1 (DARC, Duffy), ACKR2 (D6), and ACKR4 (CCRL1). The mechanisms involved in chemokine activities and the signals delivered by their receptors are described, and the clinical implications of these findings are discussed.
Clinical utilization of chemokines to combat cancer: the double-edged sword
Expert Review of Vaccines, 2007
Chemokines are a small group of related chemoattractant peptides that play an essential role in the homeostatic maintenance of the immune system. They control the recruitment of cells needed for the induction and activation of innate and adaptive immune responses. However, tumors also utilize chemokines to actively progress and evade immunosurveillance. In fact, chemokines are involved directly or indirectly in almost every aspect of tumorigenesis. They mediate survival and metastatic spread of tumors, promote new blood vessel formation (neovascularization) and induce an immunosuppressive microenvironment via recruitment of immunosuppressive cells. As a result, a number of therapeutic strategies have been proposed to target almost every step of the chemokine/ chemokine receptor involvement in tumors. Yet, despite occasional success stories, most of them appear to be ineffective or impractical, presumably due to 'nonspecific' harm of cells needed for the elimination of tumor escapees and maintenance of immunological memory. The strategy would only be effective if it also promoted antitumor adaptive immune responses capable of combating a residual disease and tumor relapse.
Cytokine and Chemokine Signals of T-Cell Exclusion in Tumors
Frontiers in Immunology, 2020
The success of cancer immunotherapy in solid tumors depends on a sufficient distribution of effector T cells into malignant lesions. However, immune-cold tumors utilize many T-cell exclusion mechanisms to resist immunotherapy. T cells have to go through three steps to fight against tumors: trafficking to the tumor core, surviving and expanding, and maintaining the memory phenotype for long-lasting responses. Cytokines and chemokines play critical roles in modulating the recruitment of T cells and the overall cellular compositions of the tumor microenvironment. Manipulating the cytokine or chemokine environment has brought success in preclinical models and early-stage clinical trials. However, depending on the immune context, the same cytokine or chemokine signals may exhibit either antitumor or protumor activities and induce unwanted side effects. Therefore, a comprehensive understanding of the cytokine and chemokine signals is the premise of overcoming T-cell exclusion for effectiv...
The Next Challenge in Cancer Immunotherapy: Controlling T-Cell Traffic to the Tumor
Cancer Research, 2012
One of the steps that limits the efficacy of T-cell-based immunotherapy of cancer is T-cell access to the tumor. We recently showed that several chemotherapeutic drugs induce intratumoral expression of chemokines that attract effector T cells. Moreover, in a cohort of patients with melanoma who had been treated with dacarbazine, one of the most frequently used chemotherapies for metastatic melanoma, tumor response to the treatment correlated with intratumoral expression of T-cell-attracting chemokines and with T-cell infiltration. These findings reveal the possibility of developing novel systemic strategies aimed at improving T-cell homing to tumors. Such strategies, used alone or in combination with adoptive T-cell therapies or therapeutic cancer vaccines, may prove to be more efficient in prolonging patient survival. Cancer Res; 72(9); 2159-61. Ó2012 AACR.