The Chemokine System in Oncogenic Pathways Driven by Viruses: Perspectives for Cancer Immunotherapy

Abstract

Chemokines interact with glycosaminoglycans of the extracellular matrix and activate heptahelical cellular receptors that mainly consist of G Protein-Coupled Receptors and a few atypical receptors also with decoy activity. They are well-described targets of oncogenic pathways and key players in cancer development, invasiveness, and metastasis acting both at the level of cancer cells and cells of the tumor microenvironment. Hence, they can regulate cancer cell proliferation and survival and promote immune or endothelial cell migration into the tumor microenvironment. Additionally, oncogenic viruses display the potential of jeopardizing the chemokine system by encoding mimics of chemokines and receptors as well as several products such as oncogenic proteins or microRNAs that deregulate their human host transcriptome. Conversely, the chemokine system participates in the host responses that control the virus life cycle, knowing that most oncoviruses establish asymptomatic latent infections. Therefore, the deregulated expression and function of chemokines and receptors as a consequence of acquired or inherited mutations could bias oncovirus infection toward pro-oncogenic pathways. We here review these different processes and discuss the anticancer therapeutic potential of targeting chemokine availability or receptor activation, from signaling to decoy-associated functions, in combination with immunotherapies.

Keywords: cancer; chemokine; immunotherapy; oncogenic viruses.

Figure 1

Interplay between oncoviruses and the chemokine system. By modulating the expression of chemokines and their receptors and encoding for viral homologs (left part), oncoviruses can hamper the functioning of chemokines and their typical and atypical human receptors through (a) increased activation or aberrant signaling; (b) virochemokines (e.g., vCCL-1-3) and vGPCRs (e.g., ORF74) acting as ligands and receptors of their human homologs, respectively; and (c) GOF mutants of human receptors (e.g., CXCR4) or potential oligomers formed between vGPCRs and human receptors (e.g., BILF1/CXCR4).

Figure 2

Harnessing the chemokine system to modulate oncovirus cancer features. (Viro)chemokines and their receptors can be targeted to limit (a) cancer cell stemness, proliferation, and survival, (b) angiogenesis, (c) metastasis, (d) immune cell recruitment, and (e) TME composition and polarization.