Abstract 5131: The XL313 cryptic collagen epitope regulates immune checkpoint molecules by a αVβ3-integrin-associated mechanism

Abstract

Abstract Proteolytic remodeling of extracellular matrix (ECM) results in structural changes that facilitate the generation of cryptic regulatory sites that promotes angiogenesis, tumor growth and metastasis. While alterations in the biophysical characteristic of the ECM can help create a tumor permissive microenvironment, little is known concerning whether structural changes in the ECM contributes to the ability of tumors to escape immune control. Molecular insight into the signaling pathways operating in stromal cells has contributed to the development of new cancer therapies. While clear progress has been made, as indicated by the recent approvals of new therapies such as immune checkpoint inhibitors, the overall survival of patients with metastatic disease remains alarmingly low. Accumulating evidence suggests that stromal components of the tumor microenvironment may contribute to the development of multiple resistance mechanisms including adaptive immune resistance. Thus, there is an urgent need for a more detailed understanding of how immune and inflammatory mechanisms govern tumor progression in order to enhance long-term durable responses with current therapies in a larger percentage of patients. Tumor-associated macrophages (TAMs) have been suggested to play roles in tumor growth and metastasis by multiple mechanisms including structural remodeling of the ECM. TAMs may also contribute to the development of resistance to current anti-cancer therapies. Our studies indicate that distinct subsets of macrophage may facilitate the generation of the RGDKGE containing XL313 cryptic collagen epitope that promotes angiogenesis and inflammation in vivo. Here we provide the first evidence that cellular interactions with the XL313 collagen epitope may regulate immune checkpoint molecules by a αVβ3 integrin-associated mechanism. Cellular interactions with the XL313 epitope and denatured forms of collagen, which are present within the tumor microenvironment, enhanced the levels of the immune checkpoint molecules PD-L1 and LAG-3. Selective targeting of the XL313 collagen epitope with a monoclonal antibody inhibited tumor growth and metastasis and tumors from these mice exhibited reduced levels of immune checkpoint molecules. Importantly, anti-XL313 epitope antibody significantly enhanced the anti-tumor activity of anti-PD-L1 therapy in vivo. These data suggest that the XL313 epitope may play a functional role in promoting immune suppression in tumors and that selective targeting of this cryptic collagen epitope may reduce immune suppression and significantly enhance the efficacy of immune checkpoint inhibitors. Taken together, our studies are consistent with the possibility that the endogenously generated XL313 epitope may regulate tumor growth in part by facilitating the escape of tumors from immune control. Citation Format: Jennifer M. Caron, Liangru Contois, Jacquelyn Ames, Peter C. Brooks. The XL313 cryptic collagen epitope regulates immune checkpoint molecules by a αVβ3-integrin-associated mechanism. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5131.