Chemokines and their Receptors: Multifaceted Roles in Cancer Progression and Potential Value as Cancer Prognostic Markers

Abstract

Chemokines are chemotactic cytokines that mediate immune cell chemotaxis and lymphoid tissue development. Recent advances have indicated that chemokines and their cognate receptors play critical roles in cancer-related inflammation and cancer progression. On the basis of these findings, the chemokine system has become a new potential drug target for cancer immunotherapy. In this review, we summarize the essential roles of the complex network of chemokines and their receptors in cancer progression. Furthermore, we discuss the potential value of the chemokine system as a cancer prognostic marker. The chemokine system regulates the infiltration of immune cells into the tumor microenvironment, which induces both pro- and anti-immunity and promotes or suppresses tumor growth and proliferation, angiogenesis, and metastasis. Increasing evidence indicates the promising prognostic value of the chemokine system in cancer patients. While CCL2, CXCL10, and CX3CL1/CX3CR1 can serve as favorable or unfavorable prognostic factors depending on the cancer types, CCL14 and XCL1 possess good prognostic value. Other chemokines such as CXCL1, CXCL8, and CXCL12 are poor prognostic markers. Despite vast advances in our understanding of the complex nature of the chemokine system in tumor biology, knowledge about the multifaceted roles of the chemokine system in different types of cancers is still limited. Further studies are necessary to decipher distinct roles within the chemokine system in terms of cancer progression and to validate their potential value in cancer prognosis.

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+T cells

“…Our understanding of the factors that regulate tumor infiltration of CD8+ T cells is incomplete, impeding progress in improving immunotherapy efficacy. Chemokines and their GPCRs have long been in the spotlight as major drivers of T-cell attraction and trafficking; however, chemokines can also promote metastasis thus acting as two-edged swords in tumor microenvironments (Do et al, 2020). Diffusible factors that counteract Tcell attraction ("inhibitory chemokines") have remained understudied to date.…”

“…However, our understanding of the factors that dictate the trafficking of tumor-infiltrating lymphocytes (TILs), either positively or negatively, is incomplete and requires identification of new tractable targets (Anandappa et al, 2020;Sackstein et al, 2017;van der Woude et al, 2017). Chemokines through their G proteincoupled receptors (GPCRs) are major drivers of T-cell chemotaxis and trafficking and keep attracting interest as potential therapeutic targets in immuno-oncology (Chow and Luster, 2014;Do et al, 2020;Vilgelm and Richmond, 2019). Tumors evolve various strategies to evade T-cell infiltration via activation of oncogenic signaling pathways, for instance by suppressing chemokine production and signaling and/or by secreting antimigratory molecules such as Wnt ligands and TGF (Batlle and Massague, 2019;Hinshaw and Shevde, 2019;Kerdidani et al, 2019;Spranger et al, 2015).…”

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…The CXCR4 antagonist plerixafor was approved for the mobilization of hematopoietic stem cells for transplantation in patients with nHL or MM [122]. These advances have led to the recognition of CXCL12 and CXCR4 receptors as promising targets for cancer immunotherapy [3].…”

SOX4 promotes the growth and metastasis of breast cancer

“…Chemokines are polypeptides that regulate cell migration and serve as key regulators of metastasis. The levels of multiple chemokines are upregulated in the cell matrix of primary or metastatic tumors, compared to normal tissues [20][21][22][23]. In breast cancer cells, binding of chemokines to their receptors can activate the transcription of a series of downstream effector genes, resulting in the proliferation and metastasis of tumor cells.…”