Tumor resident myeloid cells (MCs) are instrumental to cancer progression and are emerging as a potential therapeutic target in many cancers. The mechanisms by which tumours regulate MCs remain poorly defined. We investigated how the CRC tumour microenvironment (TME) impacts on MCs recruitment and function.
Patients with Stage II/III CRC undergoing surgical resection were recruited (n = 21). Fresh samples of tumour and uninvolved tissue were obtained and digested to a single cell suspension. MCs were phenotyped using multi-parameter flow cytometry. We generated tumor (TCM) and normal (NCM) conditioned media from a further cohort (n = 40) and assessed levels of 16 cytokines using a multiplex assay. Finally, we designed a MC:Cell line co-culture model to investigate the molecular mechanisms that control MC function.
We found two distinct MC subsets, HLA-DRhiCD11chi and CD11bhiCD15hi, unique to the tumor tissue, dominated the CD45+ compartment. Further analysis showed that the HLA-DRhiCD11chi and the CD11bhiCD15hi were of monocyte and neutrophil origin, respectively. In support of their potential immune-regulatory and proangiogenic function, we showed that the HLA-DRhiCD11chi subset expressed ILT4, PDL1 and Tie-2. The CD11bhiCD15hi subset exhibited high levels of arginase, an enzyme involved in T cell suppression. Interestingly, both cell subsets displayed an altered chemokine receptor profile compared to their blood counterparts. Accordingly, we were able to confirm the upregulated expression of inflammatory mediators, CXCL1 (p
This study identifies two MC subsets in patients with CRC. We demonstrate that the TME recruits these cells via a complex chemokine-chemokine receptor network subsequently transforming them into a highly activated but immune-regulatory cell that favors tumor growth.
Clinical trial identification
Legal entity responsible for the study
All authors have declared no conflicts of interest.