The Role of Microenvironment Mechanics in Sarcoma Immune Evasion
Abstract
Soft-tissue sarcomas (STS) comprise a heterogeneous collection of rare mesenchymal tumors that are diagnosed in approximately 12,000 individuals in the United States annually. Importantly, available treatment options are invasive and poorly tolerated (e.g., excision/amputation, radiation, and chemotherapy). Excitingly, recent clinical studies revealed that about 40% of patients with undifferentiated pleomorphic sarcoma (UPS), a relatively common STS subtype with particularly poor outcomes, respond to the immune checkpoint inhibitor (ICI), Pembrolizumab. This new finding offers some hope for novel therapies to UPS patients. However, as with many other solid tumors the molecular underpinnings, which govern UPS patient responses to immunotherapy, remain elusive. This proposal addresses the “Biology and Etiology” Focus Area in rare soft tissue sarcomas, specifically UPS. We hope to ascertain the factors that govern sensitivity to checkpoint blockade immunotherapy and exploit that knowledge to develop combination therapies that will enhance ICI efficacy. We discovered that deregulation of the Hippo signaling pathway is critical for UPS development, and the major effector of this pathway, Yes-associated protein 1 (YAP1), is expressed at unusually high levels in UPS as well as other solid tumors. Our laboratory recently found that YAP1 mediates the deposition of collagen VI in the UPS tumor microenvironment, which helps tumors evade destruction by the immune system. Specifically, Collagen VI promotes CD8+ T cell exhaustion. This surprising result revealed that extracellular matrix proteins like collagen VI, directly communicate with CD8+ T cells to modulate their function. T cell exhaustion is an immune evasion mechanism that limits the efficacy of checkpoint therapy in solid tumors. Therefore, understanding mechanisms of exhaustion may lead to improved clinical responses to immune checkpoint blockade. Our objective is to understand the role of Collagen VI in immune evasion, toward the development of novel approaches that improve the therapeutic efficacy of checkpoint blockade. Importantly, this work will provide a methodological and conceptual foundation to understand the role of matrix proteins in CD8+ T cell function in solid tumors. We anticipate that translation of our findings to the sarcoma clinic could take 5 years or less. The reason for this relatively rapid time course is that our team has access to the precise tools necessary to develop a cell-based immunotherapy for use in combination with checkpoint inhibitors and the existence of other small molecule/antibody inhibitors that could target Collagen VI receptors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110757
Entities
People
- Tzipora Eisinger
Organizations
- United States Army
- University of Pennsylvania