Supermeres containing Discoidin Domain Receptor 1 extracellular domain promote collagen alignment and immune exclusion in microsatellite stable colorectal cancer

Vollständiger Abstract

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Abstract Immune checkpoint blockade (ICB) is an effective treatment for microsatellite instability-high (MSI-H) colorectal cancers (CRCs) that are highly infiltrated by CD8+ T cells. Microsatellite stable (MSS) CRCs are unresponsive to ICB, at least in part, due to the paucity of intratumoral CD8+ T cells. We recently identified Discoidin Domain Receptor 1 (DDR1) as one of four genes associated with CD8+ T-cell exclusion in MSS CRC. There are conflicting reports about the presence and role of the cleaved ectodomain (cECD) of DDR1 in mouse models of breast and pancreatic cancer. To explore the role of the DDR1 cECD in human CRC, we developed Collagen Alignment and Spatial Transcriptomics Analysis (CASTA), which revealed that genes involved in fibroblast contractility were associated with both DDR1 tumor expression and collagen alignment as determined by label-free second harmonic generation (2HG) imaging of the tumor collagen. Using 3D collagen co-cultures of CRC spheroids and fibroblasts, we show that DDR1 promotes collagen alignment and CD8+ T-cell exclusion. We found large amounts of DDR1 cECD in MSS CRC supermeres, 25-35 nm secreted amembranous nanoparticles. Supermeres containing DDR1 cECD were sufficient to induce contraction of human colonic fibroblasts. We propose a model in which supermeres containing DDR1 cECD promote the contraction of stromal fibroblasts in MSS CRC, leading to collagen alignment and CD8+ T-cell exclusion. These results support DDR1 cECD as an attractive therapeutic target in MSS CRC.