LRRC15: A CAF-associated stromal target for tumor microenvironment–targeted therapies

• Gene Information: LRRC15 is a type I single-pass transmembrane protein encoded by the LRRC15 gene. It contains a large extracellular leucine-rich repeat domain, a transmembrane region, and a short cytoplasmic tail.
• Protein Expression: LRRC15 is minimally expressed in most normal adult tissues but is highly expressed in activated stromal cells, especially cancer-associated fibroblasts, in multiple solid tumors.
• TME Modulation: LRRC15-positive stromal cells are associated with extracellular matrix remodeling, CAF activation, TGF-β–rich tumor stroma, immune exclusion, and immunosuppressive tumor microenvironment formation.
• Therapeutic Intervention: LRRC15-targeted strategies, including antibody-drug conjugates and other stromal-targeting therapies, aim to target LRRC15-positive CAFs and remodel the tumor microenvironment. B-NDG hLRRC15 mice support in vivo evaluation of human LRRC15-targeted therapies.

LRRC15

• The exon 2 of the mouse LRRC15 gene encoding the extracellular domain were replaced with human LRRC15 exon 2 in B-NDG hLRRC15 mice.
• The genomic region of mouse LRRC15 gene that encodes the signal peptide, transmembrane domain and cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. The chimeric LRRC15 expression is driven by endogenous mouse LRRC15 promoter, while mouse LRRC15 gene transcription and translation will be disrupted.

• Mouse LRRC15 mRNA was only detected in the skin of wild-type B-NDG mice.
• Human LRRC15 mRNA was exclusively detected in the skin of homozygous B-NDG hLRRC15 mice but not in wild-type B-NDG mice.

Strain specific analysis of LRRC15 mRNA expression in wild-type B-NDG mice and B-NDG hLRRC15 mice by RT-PCR. Skin RNA was isolated from wild-type B-NDG mice (+/+) and homozygous B-NDG hLRRC15 mice (H/H), and cDNA libraries were synthesized by reverse transcription, followed by PCR with mouse or human LRRC15 primers.