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

Abstract

Simple SummaryOncoviruses are viruses with oncogenic potential, responsible for almost 20% of human cancers worldwide. They are from various families, some of which belong to the microbial communities that inhabit several sites in the body of healthy humans. As a result, they most often establish latent infections controlled by the arsenal of human host responses that include the chemokine system playing key roles at the interface between tissue homeostasis and immune surveillance. Yet, chemokines and their receptors also contribute to oncogenic processes as they are targeted by the virus-induced deregulations of host responses and/or directly encoded by viruses. Thus, the chemokine system offers a strong rationale for therapeutic options, some few already approved or in trials, and future ones that we are discussing in view of the pharmacological approaches targeting the different functions of chemokines operating in both cancer cells and the tumor microenvironment.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.