Anti-CCR5 monoclonal antibody, clone OQ-7H5

CCR5 is a chemokine receptor that mediates the action of inflammatory cells, besides acting as an HIV coreceptor. CCR5 Delta 32 states for a genetic variant containing a 32 base pair deletion in the coding region of the CCR5 gene. In homozygosis, CCR5 Delta 32 results in the lack of CCR5 expression on the cell surface, which was associated with protection against HIV infection. Heterozygous individuals for CCR5 Delta 32 have a reduced CCR5 expression. Recent evidence demonstrates that CCR5 and CCR5 Delta 32 are involved in the pathogenesis of other viral infections besides HIV infection. Nevertheless, the role of CCR5 and CCR5 Delta 32 in HBV infection is not clear and conflicting results have been reported. Thus, the objective of this study was to investigate the role of CCR5 Delta 32 in HBV mono-infection and HBV/HIV co-infection in a population from southern Brazil. A total of 1113 individuals were evaluated, divided in controls (n = 334), HBV + (n = 335), HBV + /HIV + (n = 144), and including an HIV + group to complement the analyses (n = 300, obtained from a previous study of our research team). The CCR5 Delta 32 allele frequencies found were 7.5 %, 9.0 %, and 3.1 %, respectively for controls, HBV +, and HBV + /HIV + patients. The individuals were classified in CCR5 Delta 32 allele carriers and CCR5 Delta 32 allele non-carriers and the groups were compared using binary logistic regression adjusted for covariates. No significant effect of the CCR5 Delta 32 variant was observed on the susceptibility or protection against HBV monoinfection in individuals from southern Brazil. A potential protective effect of CCR5 Delta 32 on HBV/HIV co-infection was observed. However, it can be due to the effect of CCR5 Delta 32 in the protection against HIV infection or external factors not covered in the study. Finally, this study contributes to the understanding of the role of CCR5 in HBV infection, suggesting no effect of CCR5 Delta 32 on susceptibility to HBV mono-infection.

Multiple reports have highlighted the importance of the local immunological cellular composition (i.e. the density of effector T cells and macrophage polarization state) in predicting clinical outcome in advanced metastatic stage of colorectal cancer. However, in spite of the general association between a high effector T cell density and improved outcome, our recent work has revealed a specific lymphocyte-driven cancer cell-supporting signal. Indeed, lymphocyte-derived CCL5 supports CCR5-positive tumor cell proliferation and thereby fosters tumor growth in metastatic liver lesions. Upon systematic analysis of CCR5 expression by tumor cells using immunohistochemistry, we observed that the intensity of CCR5 increases with primary tumor size and peaks in T4 tumors. In liver metastases however, though CCR5 expression intensity is globally heightened compared to primary tumors, alterations in the expression patterns appear, leading to "patchiness" of the stain. CCR5 patchiness is, therefore, a signature of liver metastases in our cohort (n = 97 specimens) and relates to globally decreased expression intensity, but does not influence the extent of the response to CCR5 inhibitor Maraviroc in patients. Moreover, CCR5 patchiness relates to a poor immune landscape characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin and enriched cellular and molecular markers of macrophage M2 polarization. Finally, because higher numbers of PD-1- and CTLA-4-positive cells surround tumors with patchy CCR5 expression, one can speculate that these tumors potentially respond to immune checkpoint blockade. This hypothesis is corroborated by the prolonged disease-free survival and disease-specific survival observed in patients with low gene expression of CCR5 in metastases from two publically available cohorts. These observations highlight the complex role of the CCL5-CCR5 axis in CRC metastatic progression and warrant further investigations.