The microenvironment of DLBCL is characterized by non-canonical macrophages recruited by tumor-derived CCL5.

Tissue invasion by tumor cells induces a host inflammatory response variably impacting tumorigenesis. This has been well documented for tumor-associated macrophages (TAM) that could either play a pro/M2 or an anti/M1-tumoral function. TAM frequently infiltrate diffuse large B-cell lymphoma (DLBCL), an aggressive neoplasm arising from germinal center-experienced B cells. However, the pathway leading to TAM presence in DLBCL remains unknown and their impact unclear. Here, we show that some DLBCL tumor cells expressed the chemokine CCL5, enabling the differential recruitment of blood monocytes through their expression of CCR1 and CCR5. CCL5 expression by DLBCL was not related to molecular subtypes and healthy tonsillar B cells did not produce this chemokine, implying a post-transformation event. A single-cell analysis revealed that most DLBCL TAM had a non-canonical gene signature with the concomitant expression of M1 and M2 genes. The presence of non-canonical TAM may explain the absence of impact reported for macrophages on DLBCL development in some survival studies.