Abstract
Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFβ on activated fibroblasts (αSMA+) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80+ macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.Significance: These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma. Cancer Res; 78(14); 4059-72. ©2018 AACR.
Highlights
Many cancer types with high stromal content, such as pancreatic cancer, triple-negative breast cancer, non–small cell lung cancer (NSCLC) and sarcoma, continue to have low response rates to current therapies and poor long-term survival [1,2,3]
It has been proposed that extracellular matrix (ECM) proteins generated by cancer-associated fibroblasts (CAF) found in tumor stroma impede the effective uptake of traditional chemotherapeutics, and contribute to the immunosuppressive environment seen in most solid tumors [4,5,6,7]
leucine-rich repeat containing 15 (LRRC15) is highly expressed in tumor stroma and on cancer cells of mesenchymal origin
Summary
Many cancer types with high stromal content, such as pancreatic cancer, triple-negative breast cancer, non–small cell lung cancer (NSCLC) and sarcoma, continue to have low response rates to current therapies and poor long-term survival [1,2,3]. It has been proposed that extracellular matrix (ECM) proteins generated by cancer-associated fibroblasts (CAF) found in tumor stroma impede the effective uptake of traditional chemotherapeutics, and contribute to the immunosuppressive environment seen in most solid tumors [4,5,6,7]. Disrupting the ECM to improve drug delivery is a strategy that is being pursued preclinically as well as in early clinical trials in stroma-rich tumors such as pancreatic cancer [8,9,10]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). J.W. Purcell and S.G. Tanlimco contributed to this work
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