ADGRL4/ELTD1 Expression in Breast Cancer Cells Induces Vascular Normalization and Immune Suppression

Abstract

ELTD1/ADGRL4 expression is increased in the vasculature of a number of tumor types and this correlates with a good prognosis. Expression has also been reported in some tumor cells with high expression correlating with a good prognosis in hepatocellular carcinoma (HCC) and a poor prognosis in glioblastoma. Here we show that 35% of primary human breast tumors stain positively for ELTD1, with 9% having high expression that correlates with improved relapse-free survival. Using immunocompetent, syngeneic mouse breast cancer models we found that tumors expressing recombinant murine Eltd1 grew faster than controls, with an enhanced ability to metastasize and promote systemic immune effects. The Eltd1-expressing tumors had larger and better perfused vessels and tumor–endothelial cell interaction led to the release of proangiogenic and immune-modulating factors. M2-like macrophages increased in the stroma along with expression of programmed death-ligand 1 (PD-L1) on tumor and immune cells, to create an immunosuppressive microenvironment that allowed Eltd1-regulated tumor growth in the presence of an NY-ESO-1–specific immune response. Eltd1-positive tumors also responded better to chemotherapy which could explain the relationship to a good prognosis observed in primary human cases. Thus, ELTD1 expression may enhance delivery of therapeutic antibodies to reverse the immunosuppression and increase response to chemotherapy and radiotherapy in this subset of tumors. ELTD1 may be useful as a selection marker for such therapies. Implications: ELTD1 expression in mouse breast tumors creates an immunosuppressive microenvironment and increases vessel size and perfusion. Its expression may enhance the delivery of therapies targeting the immune system.

Single-cell pair-wise relationships untangled by composite embedding model

“…Previously known that PECAM1 , CALCR , ADGRL4 , and CD93 genes are predominantly expressed in endothelial cells and regulate angiogenesis in tumor cells. 38 In addition, TME-regulation associated primarily consisted of genes mixture of endothelial-associated and stroma-associated topics with enrichment of distinct genes known to control tumor growth and promote stemness of cancer cells in microenvironment such as KCNN4 , IL6ST , and CD1B . 39 Furthermore, we observed a significant overlap between the gene-gene interactions derived from the interaction topic model and the gene network in the STRING database.…”

Single-cell Pairwise Relationships Untangled by Composite Embedding model

“…Similarly, genes enriched in the endothelial topic recapitulate interactions of cancer cells in developing tumour vascular networks, especially in conjunction with endothelial cells. Previously known that PECAM1, CALCR, ADGRL4 , and CD93 genes are predominantly expressed in endothelial cells and regulate angiogenesis in tumour cells [Sheldon et al, 2021]. Additionally, TME-regulation associated topic primarily consisted of genes mixture of endothelial-associated and stroma-associated topics with enrichment of distinct genes known to control tumour growth and promote stemness of cancer cells in microenvironment such as KCNN4, IL6ST , and CD1B [Fan et al, 2022].…”

Single-cell analysis reveals ADGRL4+ renal tubule cells as a highly aggressive cell type in clear cell renal cell carcinoma

“…Huang et al 31 showed that targeting ADGRL4/ ELTD1 restores vascular function and improves prognosis in gliomas. A mouse breast cancer model with recombinant ADGRL4/ELTD1 expression exhibits metastasis to lung, more tumorous tissues and larger tumor vascular size 32 . In metastatic renal cell cancer, patients with high ADGRL4/ELTD1 expression in the tumor vasculature respond better to sunitinib treatment 33 .…”