Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy

Abstract

Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the "inflamed" immune-cell enriched tumor microenvironment. 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. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.

Keywords: cancer; chemokine; chemokine receptor; immune surveillance; immune therapy; metastasis.

Figure 1

The chemokine family of chemokine ligands and chemokine receptors. The XC chemokine receptor is in green, CC chemokine receptors are in blue B, CX3CR chemokine receptor is in yellow, and CXC chemokine receptors are in lilac. 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. B, B cell; iDC, immature DC; NK, natural killer cell; NKT, natural killer T cell; MDSCs, myeloid-derived suppressor cells; pDC, plasmacytoid DC; Th, T helper cell; T_CM, central memory T cell; T_EFF, effector T cell; T_FH, follicular helper T cell; T_FR, follicular regulatory T cell; T_N, naïve T cells, T_RCM, recirculating memory T cell (11, 12).

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.

Figure 3

Chemokines associated with patient survival in various malignancies. Prognostic data was obtained from The Human Protein Atlas. We reviewed Kaplan-Meier plots for all cancers where high expression of indicated chemokine genes has significant (p < 0.001) association with patient survival. Based on this review we constructed a table where chemokines associated with better survival in one of the reviewed malignancies were assigned the value of “1.” Chemokines that were significantly associated with worse survival in a given malignancy were assigned the value of “−1.” Chemokines not strongly associated with survival (p > 0.001) were assigned the value of “0.” Chemokines that were not prognostic in any of the tested malignancies were excluded. Based on the resulting table the heat map was constructed using Morpheus online tool (https://software.broadinstitute.org/morpheus).