DDR1 functions as an immune negative factor in colorectal cancer by regulating tumor‐infiltrating T cells through IL‐18

Abstract

Immunotherapies represented by programmed cell death protein 1/programmed cell death ligand 1 (PD‐1/PD‐L1) immune checkpoint inhibitors have made great progress in the field of anticancer treatment, but most colorectal cancer patients do not benefit from immunotherapy. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, is activated by collagen binding and overexpressed in various malignancies. However, the role of DDR1 in colorectal cancer and immunoregulation remains unclear. In this study, we found DDR1 is highly expressed in colorectal cancer tissues and negatively associated with patient survival. We demonstrated that DDR1 promotes colorectal tumor growth only in vivo. Mechanistically, DDR1 is a negative immunomodulator in colorectal cancer and is involved in low infiltration of CD4+ and CD8+ T cells by inhibiting IL‐18 synthesis. We also reported that DDR1 enhances the expression of PD‐L1 through activating the c‐Jun amino terminal kinase (JNK) signaling pathway. In conclusion, our findings elucidate the immunosuppressive role of DDR1 in colorectal cancer, which may represent a novel target to enhance the efficacy of immunotherapy in colorectal cancer.

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors

“…Surveying other gene signatures, we identified additional programs that coincided with IES such as pEMT and oxidative metabolism, which are hallmarks of advanced cancer and upregulated during tumor progression, validating the emergence of IES in late PPT (Figure 5C; Figure S5B). Moreover, fibrosis and hypoxia signatures correlated with IES at the patient-level, lending credence to the involvement of constituent genes in ECM signaling and regulation as these characteristics are implicated in microenvironmental immunosuppression 70,26,27,71,75 (Figure 5C; Figure S5D). Most importantly, this four-gene IES had a negative correlation with cytotoxic T cells (TL2) and with the CD8 T cell signature score across all tumor regions in the dataset, indicating its value as a predictor of immune exclusion 62 (Figure 5B).…”

“…These genes originate from epithelial cells, which implicated a mechanism of microenvironmental modulation by the tumor itself. Each of these genes has also been shown to associate with immune exclusion in several solid tumor types, providing an interesting, concerted signature that potentially creates an immune-tolerant environment in CIN+ CRC 70,26,27,71 .…”

“…PPT models enabled the unbiased identification of gene programs relevant to tissue dynamics along tumor development, and allowed us to assemble an epithelial-intrinsic Immune Exclusion Signature (IES) defined by expression of DDR1, TGFBI, PAK4, and DPEP1. This aggregated signature is highly informative, as these genes have been implicated separately as immune modulators but not always in the context of CRC 26,91,92,71 . DDR1 has been reported to align collagen fibers in a way that excludes T cells from the breast TME 27 .…”

“…These genes originate from epithelial cells, which implicated a mechanism of microenvironmental modulation by the tumor itself. Each of these genes has also been shown to associate with immune exclusion in several solid tumor types, providing an interesting, concerted signature that potentially creates an immunetolerant environment in CIN+ CRC 70,26,27,71 . Additionally, we observed a significant increase in DPEP1 expression with CIN+ PPT, a gene which was also highly enriched in the CRC2 epithelial state (Figure 5A; Figure 4H; Figure S4C-D).…”

Oncogene-induced matrix reorganization controls CD8+T cell function in the soft-tissue sarcoma microenvironment

“…We excluded the possibility that Lair1 may be involved given it was not expressed on CD8 + T cells in KP tumors. Similarly, the involvement of another ColI receptor, Ddr1, is unlikely, given Ddr1's previously reported role in the negative regulation of CD8 + T cell migration/infiltration in carcinomas (87,88). Conversely, certain ColI-binding integrins such as Itga1, Itgav, and Itgb1 may be candidates given their putative roles in/associations with promoting CD8 + T activity (89)(90)(91)(92).…”