Multidimensional imaging provides evidence for down regulation of T cell effector function by MDSC in human cancer tissue
Intratumoral physical engagement of T cells with immunosuppressive neutrophils is associated with reduced effector function. Interior tumor views Previous studies indicate that a high frequency of intratumoral neutrophils is associated with a poor clinical prognosis. Si et al. used a variety of microscopy and imaging techniques to examine how intratumoral interactions between tumor associated neutrophils (TANs) and tumor infiltrating lymphocytes (TILs) can affect TIL function. They developed 2D and 3D multiparameter immunofluorescence imaging techniques to localize and define functional cell subsets, which were used to identify hotspots of TAN/TIL interactions within tumors. Some of these TANs had a polymorphonuclear myeloid derived suppressor cell (PMN MDSC) phenotype, and their physical association with TILs reduced antitumor functions of those TILs. This study identifies areas of MDSC activity in human tumors and provides a more detailed perspective of how intratumoral cell interactions influence cell function. 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.
Science Immunology