New information about the biological role of chemokines in these cancer related processes is providing insights into host—tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Chemokines are chemotactic cytokines that cause the directed migration of leukocytes, and are induced by inflammatory cytokines, growth factors and pathogenic stimuli.
Chemokine signalling results in the transcription of target genes that are involved in cell invasion, motility, interactions with the extracellular matrix ECM and survival. Chemokine signalling can coordinate cell movement during inflammation, as well as the homeostatic transport of haematopoietic stem cells HSCs , lymphocytes and dendritic cells. Directed migration of cells that express the appropriate chemokine receptor occurs along a chemokine gradient — allowing cells to move towards high local concentrations of chemokines. Figure 1 Diagram of a chemokine gradient in a cancer.
An inflammatory cytokine induces chemokine production by an epithelial tumour cell.
A macrophage that expresses the corresponding receptor binds the chemokine and undergoes rapid cytoskeletal rearrangement. This is followed by induction of a transcriptional programme that favours cell migration — for example, induction of matrix metalloproteinases MMPs — and cell survival.
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The cell migrates towards a higher concentration of chemokine. As the chemokine concentration increases, the chemokine receptor can be downregulated. Alternatively, the chemokine-receptor profile of the cell might change under the influence of other inflammatory cytokines or local conditions. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment.
Chemokines in Cancer
In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.
Migration of the immune cells to specific organs is controlled in part by small proteins called chemokines i. Chemokines bind to seven transmembrane G protein-coupled receptors that trigger intracellular signaling that drives cell polarization, adhesion, and migration 3 , 4. The receptors follow a similar nomenclature system, based upon the family of chemokines to which they bind.
In addition there is a family of atypical chemokine receptors that do not directly couple to G proteins, but are reported to have a variety of roles in development, homeostasis, inflammatory disease, infection, and cancer 5. Chemokines are also classified as homeostatic or inflammatory 4 , 6 — 8 and both subsets play important roles in cancer 9 , Since chemokines and their receptors are highly promiscuous, with most chemokines binding multiple receptors, and receptors binding multiple chemokine ligands.
One must consider this complexity in reference to functional significance of each chemokine or receptor in reference to cancers Figure 1. Figure 1. The chemokine family of chemokine ligands and chemokine receptors.
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The inner lines leading to each chemokine receptor shows the ligands that bind to the receptor. Outside the chemokine receptor wheel shows the types of cells that express the receptor to respond to the ligands for each chemokine receptor. Because the same chemokines that recruit anti-tumor leukocytes can also recruit pro-tumor leukocytes for example CCL19 and CCL21 recruit both Tregs, mDCs, and activated T cells , therapeutically targeting chemokines or chemokine receptors in cancer is complicated.
The clone subsequently expands in response to IL-2 induced stimulation of cell proliferation.
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Different subsets of T cells migrate in response to a variety of chemokines CCL21 is presented by heparin sulfate into the luminal surface These cells produced IL-2 when there is restimulation Additional interactions of chemokines and chemokine receptors that facilitate recruitment of diverse immune cells are shown in Figure 1. Figure 2. Chemokines produced by stromal cells, tumor cells, and immune cells dynamically modulate the immune landscape of the tumor microenvironment. Dashed red lines indicate a cell moving toward a chemokine gradient. Solid T red lines indicate inhibition.
Solid black lines indicate chemokines released by a cell type. Solid black T lines indicate immune cell killing of tumor cells. This diagram includes representative chemokines recruiting immune cells but does not include all possible interactions. However, same chemokines can be either favorable or unfavorable prognostic indicators depending on the type of malignancies.
CXCL9 is also favorable in endometrial and breast cancer. Elevated expression of CXCL1 is unfavorable indicator in renal, liver and cervical cancers, but it is favorable in breast cancer. High expression of CCL4 and CCL5 are associated with better outcome in melanoma, endometrial, and colorectal cancer, but with worst outcome in renal cancer Figure 3. Moreover, loss of CCL5 expression was found to be associated with enhanced melanoma aggressiveness 77 and poor therapeutic response Interestingly, tumor genomic instability can affect chemokine expression and patients' outcome.
For instance, chromosomal instability in colorectal cancer can lead to deletion of the CXCL13 gene which is associated with greater risk of tumor relapse Of note, in human breast cancer CXCL13 is produced by follicular helper T cells which are linked with activation of adaptive antitumor humoral responses Figure 3. Chemokines associated with patient survival in various malignancies.
Prognostic data was obtained from The Human Protein Atlas. Thus, primary tumor data indicate that chemokines play an important role in tumor progression, which, in part, may relate to the direct effect of chemokines on cancer cell growth and metastasis 9.
However, the main effect of chemokines is likely due to their ability to recruit specific subtypes of immune cells into the tumor that, in turn, can modulate tumor growth and metastasis. This study showed that genes associated with immune cells, especially T cells, are the most significant indicators of favorable patient outcome Furthermore, the presence of T cells or T cell expression signature within the tumor is associated with greater likelihood of response to immune checkpoint inhibitors 22 , 76 , 82 — Below we summarize recent studies demonstrating that chemokine-mediated recruitment plays a central role in the regulation of the levels of different immune subtypes within the tumor.
Tumor cells express a wide range of chemokine receptors, and there are extensive reports that tumor cells utilize both autocrine and paracrine pathways to respond to chemokines with altered migration, proliferation, and gene expression. Importantly, chemokine receptors have been reported to play a crucial role in maintenance of cancer stem cells. For example, a CXCR1 blockade has been shown to selectively target breast cancer stem cells 86 and its expression has been correlated with poor prognosis in breast cancer Similarly, CCL2 expression by cancer-associated fibroblasts has been shown to support the growth of breast cancer stem cells 92 , while CXCR4 was shown to be enriched in a subset of glioma cancer stem cells Furthermore, expression of the CXCR4 ligand, CXCL12, by tumor-associated fibroblasts has been shown to promote immune evasion in a murine model of pancreatic cancer, while targeting CXCR4 with specific antagonist AMD facilitated immunotherapy response in these model CCR5 has also been implicated in breast cancer growth and metastasis 98 — These findings provide a rationale for targeting these chemokine receptors within the tumor microenvironment.
Granot et al. Tumor entrained neutrophils inhibit seeding in the pre-metastatic lung In contrast, Lavender reported that while in vitro delivery of CCL2 to 4T1 TENs enhanced the killing of the less aggressive 67NR variant of 4T1 tumor cells, intranasal delivery of CCL2 enhanced the seeding and outgrowth of tumor cells in the lung Presumably, the contribution of different chemokines to tumor growth and metastasis may be context dependent reflecting the overall complexity of cancer-associated chemokine-chemokine receptor network.
Cytotoxic CD8 T cells are Th1-differentiated CD4 T cells are the main drivers of anti-tumor immunity, and there is a strong clinical and experimental evidence that chemokines are necessary to for the recruitment of these cells into the tumor. Analysis of patient samples indicates that chemokine expression is associated with T cell infiltrate.
The critical role of CXCR3 ligands in the recruitment of T cells into tumors of various origin has been well-documented 4. This critical role was further confirmed by the recent meta-analysis study which examined 5, cancer specimens from breast, colorectal, lung, ovary, melanoma, and head and neck carcinomas.
Interestingly, this study also uncovered a surprising negative correlation between the expression of CXCR3 ligands and neutrophil levels within tumors, indicating a possibility of a mutually exclusive pattern of T cell and neutrophil recruitment.
Furthermore, B16 melanoma tumors grow more rapidly in mice lacking CXCR3, and their tumors have lower levels of T cells as compared to wild-type mice. Interestingly, there is evidence that tumors can find ways to neutralize anti-tumor chemokines within the tumor microenvironment. For example, a study Barreira da Silva et al. These findings suggest that DPP4 inhibitors which are used as anti-diabetic drugs could potentially be used to stimulate tumor immunity. Certain C-C chemokines can also contribute to T cell recruitment into the tumor.
However, mouse studies showed that CCR5 is dispensable for homing of T cells into melanoma Recent studies indicate the critical role of CCL4 and CCL5 within the tumor microenvironment is the recruitment of cells of myeloid lineage that support adaptive anti-tumor T cell responses, such as dendritic cells. Furthermore, tumor-derived CCL4 has also been linked with the recruitment of DC cells in a mouse model of melanoma.
Similar data were obtained in urothelial bladder cancer Sinusoidal endothelial cells were the major source of CXCL16 which was induced by gut microbiome-mediated primary-to-secondary bile acid conversion Cremonesi et al. Expression of these chemokines was induced upon exposure of patient-derived colorectal cancer cells to gut microbiota and thus was sensitive to antibiotic treatment. These chemokines predominantly induced recruitment of T cells with an anti-tumor activity which was associated with improved survival in an animal model and clinical samples These reports suggest that many different chemokines contribute to anti-tumoral T cell recruitment.
However, experimental evidence suggests that not all of these chemokines directly regulate T cell chemotaxis. For instance, an in vivo analysis of anti-tumoral T cell chemotaxis using competitive homing assay showed that key tumor-derived chemotactic factors are CXCR3 ligands, while CCL5, which was also produced by melanoma tumors, is dispensable for direct homing of T cells into the tumor Furthermore, as shown by Yagawa et al.
These data suggest that the observed correlation of T cell markers and CCL5 observed in human melanoma tumors could be a result of indirect promotion of T cell recruitment or proliferation by myeloid and antigen-presenting cells recruited by CCL4 and CCL5.
Differences Between Chemokines and Cytokines - BiologicsCorp
Notably, some chemokines may even play a role in repelling T cells as shown by Li et al. It is not yet fully understood why immune cells are present in some but absent in other tumors. It has been hypothesized that tumors with high mutation burden are more immunogenic because peptides derived from mutated proteins can serve as neo-antigens when bound by MHC molecules for presentation to T cells and thus can trigger an immune response , However, a study of a TCGA tumor sample collection found no correlation between the T cell gene expression signature and mutational burden in any cancer type An explanation of this interesting data came from the recent study by Cristescu et al.
This study found that tumor mutational burden and a T cell-inflamed gene expression profile were independently predictive of response to the PD-1 antibody pembrolizumab. Notably, these parameters demonstrated a low correlation between each other, suggesting that they reflect distinct features of tumors that independently promote immunotherapy response. These data suggest that many tumors, including potentially immunogenic tumors with high mutation burden, find ways to exclude immune cells to escape immune-mediated destruction.
Indeed, regardless of the mutational load and ability to produce neo-antigen peptides, if tumor antigen-specific T cells are not mobilized to infiltrate the tumor, the presence of mutations and neoantigens is not going to be sufficient to mount anti-tumor immunity. Based on this logic, chemokines are likely to facilitate immunotherapy responses by bringing immune cells with anti-tumor activity into the tumor and, thus, counteracting T cell exclusion.
The data from patients' samples supports this hypothesis. For example, Ayers et al. Furthermore, a Genentech-sponsored study of therapeutic anti-PD-L1 antibody showed a significant positive correlation between therapeutic response and baseline CXCL9 levels in melanoma. This correlation, however, did not reach statistical significance in NSCLC or renal carcinoma tumors This is an unexpected finding because this chemokine is generally associated with T-cell infiltration. For instance, functional mouse studies revealed the requirement of CXCR3 ligands for response to anti-TIM-3 immune checkpoint inhibitor when administered in combination with chemotherapeutic drug paclitaxel Of course, not all chemokines play a beneficial role in immunotherapy outcome.
The key question that remains is how the expression of immunotherapy response-promoting chemokines is induced in tumors? The rationale for this study relates to the fact that PD-L1 positive tumors are more likely to respond to anti-PD-L1 immunotherapy, even though PD-L1 is not a definitive predictor of response , Perhaps both mechanisms take place in vivo. Furthermore, Benci et al.
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