Antigen-presenting cells (APCs) such as macrophages and dendritic cells are also recruited into the tumour microenvironment, and they can activate and expand the local effector immune cells, thereby promoting tumour regression. The recruitment of TH17 cells Human TH17 cells express high levels of CC-chemokine receptor 6 (CCR6), CXCR4, multiple CD49 integrins and the C-type lectin-like receptor CD161 (REFS 17,20C22). immune cell trafficking and lymphoid tissue development1,2. The chemokines are the largest subfamily of cytokines and can be further subdivided into four main classes depending on the location of the first two cysteine (C) residues in their protein sequence: namely, the CC-chemokines, the CXC-chemokines, C-chemokines and CX3C-chemokines2. There is an important degree of redundancy in the chemokine superfamily, with many ligands binding different receptors and vice versa2 (FIG. 1). In the tumour microenvironment, chemokines can be expressed by tumour cells and other cells, including immune cells and stromal cells. In response to specific chemokines, different immune cell subsets migrate into the tumour microenvironment and regulate tumour immune responses in a spatiotemporal manner. In addition, chemokines can directly target non-immune cells including Benzocaine tumour cells and vascular endothelial cells in the tumour microenvironment, and they have been shown to regulate tumour cell proliferation, malignancy stem-like cell properties, malignancy invasiveness and meta stasis. Therefore, chemokines directly and indirectly impact tumour immunity; shape tumour immune and biological phenotypes; and influence cancer progression, therapy and patient outcomes3C10 (FIG. 1). In this Review, we describe the expression patterns and regulation of the main chemokines that are found in the human malignancy microenvironment, and their effects on immune cells and non-immune cells. There has recently been a huge amount of research on malignancy immunology and immunotherapy10,11, and here we discuss whether selectively targeting chemokineCchemokine receptor signalling could match and increase the efficacy of the immunotherapies that are currently being used in cancer treatment3,4,10,12. Open in a separate window Figure 1 Chemokine receptor and Rabbit polyclonal to SHP-1.The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. ligand pairingsThe chemokine receptors and ligands that belong to each of the main chemokine families (namely, the C-, CC-, CXC- and CX3C-chemokine families) are shown. Blue and red boxes represent chemokineCchemokine receptor interactions that occur in mice and humans, respectively, and the non-boxed interactions occur in both humans and mice. Abbreviations enclosed in parentheses indicate alternative names for the preceding chemokine or chemokine receptor. Question marks indicate that the respective chemokine receptor is currently unknown. Immune cell tumour trafficking Different lymphocytes traffic into the tumour microenvironment, and they can modulate tumour immune responses in both primary tumours and metastatic sites. Here, we discuss several key chemokine networks that regulate lymphocyte recruitment into the tumour microenvironment, and discuss how the recruited lymphocyte subsets regulate tumour immunity and tumorigenesis. The recruitment of effector T cells and natural killer cells CD8+ T cells that are specific for tumour-associated antigens (TAAs) can engage tumour cells in an antigen-specific manner, and they drive antitumour immunity by secreting effector cytokines, releasing cytotoxic molecules (such as granzyme B and perforin) and inducing apoptosis in tumour cells. In addition to CD8+ T cells, interferon- (IFN)-expressing T helper 1 (TH1) cells Benzocaine and natural killer (NK) cells have potent antitumour effects in the tumour microenvironment. Effector CD8+ T cells, TH1 cells and NK cells express CXC-chemokine receptor 3 (CXCR3), which is the receptor for the TH1-type chemokines CXC-chemokine ligand 9 (CXCL9) and CXCL10, and they can migrate into tumours in response to these chemokines (FIG. 2). Increased levels of CXCL9 Benzocaine and CXCL10 are associated with increased numbers of tumour-infiltrating CD8+ T cells, and correlate with decreased levels of cancer metastasis and improved survival in patients with ovarian cancer and colon cancer13C18. Recent studies have demonstrated that tumour-infiltrating CD8+ T cells and intratumoural TH1-type chemokines are associated with positive responses to therapeutic blockade of the immune checkpoint molecules programmed cell death protein 1 (PD1) Benzocaine and PD1 ligand 1 (PDL1; also known as B7-H1)10. Interestingly, CD8+ T cells in the tumour microenvironment were shown recently to regulate the metabolism of the chemotherapeutic agent cisplatin by fibroblasts in ovarian cancer19. In this study, CD8+ T cell-derived IFN altered glutathione and cysteine metabolism in fibroblasts, and abolished their resistance.