Multidimensional imaging provides evidence for down-regulation of T cell effector function by MDSC in human cancer tissue

Abstract

A high intratumoral frequency of neutrophils is associated with poor clinical outcome in most cancer entities. It is hypothesized that immunosuppressive MDSC (myeloid-derived suppressor cell) activity of neutrophils against tumor-reactive T cells contributes to this effect. However, direct evidence for such activity in situ is lacking. Here, we used whole-mount labeling and clearing, three-dimensional (3D) light sheet microscopy and digital image reconstruction supplemented by 2D multiparameter immunofluorescence, for in situ analyses of potential MDSC–T cell interactions in primary human head and neck cancer tissue. We could identify intratumoral hotspots of high polymorphonuclear (PMN)–MDSC and T cell colocalization. In these areas, the expression of effector molecules Granzyme B and Ki67 in T cells was strongly reduced, in particular for T cells that were in close proximity or physically engaged with PMN-MDSC, which expressed LOX-1 and arginase I. Patients with cancer with evidence for strong down-regulation of T cell function by PMN-MDSC had significantly impaired survival. In summary, our approach identifies areas of clinically relevant functional interaction between MDSC and T cells in human cancer tissue and may help to inform patient selection in future combination immunotherapies.