4th Immunotherapy of Cancer Conference (ITOC4), March 20–22, 2017, Prague, Czech Republic

Colorectal cancer is a devastating disease, especially for patients with unresectablemetastatic lesions. Niels Halama (Heidelberg, Germany) and colleagues set out to investigate the local immunologicalmicroenvironment in colorectal cancer liver metastases. With a sophisticated approach utilizing whole slide image quantification and multiplex proteomics, the spatial profile revealed an unexpected relationship between lymphocytes and tumor cells. Further experiments showed a tumor-promoting role for CD4 and CD8 T lymphocytes in metastatic colorectal cancer that directly elicit proliferation and production of protumorigenic inflammatory cytokines mediated by the chemokine axis CCL5-CCR5. Tumor promotion is induced by enhanced migratory properties of tumor cells and pro-metastatic factors produced by tumor-associated macrophages. A newly developed fully human tumor explant model system allowed systematic functional characterization and showed effective abrogation of this pathomechanism by a selective CCR5 inhibitor. Blocking CCR5 leads to antitumoral repolarization of macrophages in the microenvironment. Translation into a clinical trial with advanced metastatic colorectal cancer patients confirmed the therapeutic efficacy of CCR5 blockade, especially in mitigating this pro-tumor inflammatory microenvironment through effects on both tumor cells and tumor-associated macrophages. This prospective trial also validated the predictions of the explant model system and therefore highlights the possibilities of this strategy for translational research.