Abstract
Immune surveillance of tumour cells is an important function of CD8 T lymphocytes, which has failed in cancer for reasons still unknown in many respect but mainly related to cellular processes in the tumour microenvironment. Applying imaging cycler microscopy to analyse the immune contexture in a human skin cancer we could identify and map 7,000 distinct cell surface-associated multi-protein assemblies. The resulting combinatorial geometry-based high-functional resolution led to discovery of a mechanism of T cell trapping in the epidermis, which involves SPIKE, a network of suprabasal keratinocyte projections piercing and interconnecting CD8 T cells. It appears initiated by clusters of infrabasal T and dendritic cells connected via cell projections across a fractured basal lamina to suprabasal keratinocytes and T lymphocytes.
Highlights
Fig. 2; the complete combinatorial molecular phenotypes (CMPs) list in provided in Supplementary Table 2)
Imaging cycler microscopy (ICM) was performed with a robotic system programmed to run repetitive cycles of staining, imaging and bleaching of a FITC-conjugated tag library to collect z-stack images of every detected protein of a Mycosis fungoides (MF) tissue section placed on the stage of the ICM epifluorescence scanning table[32]
The resulting combinatorial molecular phenotypes (CMPs) per voxel were assembled as frequency matrix (Supplementary Table 2 and 3) sorted by motifs with lead proteins present in all CMPs of the respective motif, and mapped to and visualized at their tissue locations as previously described[32]
Summary
Fig. 2; the complete CMP list in provided in Supplementary Table 2). A long cell projection (arrow 1 in a) of Cells 3,4,5 extends from the dermis across the basal lamina (a, BL) into the epidermis where it is closely opposed to a CD8+CD3+ T cell (Cell 2 in a,c,d; brown color in d) and a neighboring keratinocyte (Cell 1 in a,c,d). (e) details of the suprabasal part of this structure pictured from different angles (e,f,g,h). Disclosed a hitherto unknown multicellular structure, which we dissected spatially using a real-time virtual anatomical slicing technique. This approach revealed direct insight into an unexpected structure and mechanism of mechanical trapping of suprabasal non-tumour CD8 T cells through keratinocyte-mediated piercing, interconnecting and fixing these cells with infrabasal cells in the dermis. This entire multicellular assembly constitutes a systems-robustness node protecting the tumour from cytotoxic T cell attack
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