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.