Targeting exosomal PDL1 to improve immunotherapy

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Project Summary - Project 1 Immune checkpoint inhibitors (ICI) such as anti-PD-1 antibodies have revolutionized anti-tumor therapy for many types of cancers including metastatic melanoma. However, the patient response rates are low. Combined therapies such as ipilimumab and nivolumab produce a higher response rate but are associated with significant toxicities. A major unmet need is to develop quantitative assays that stratify patients who will respond to anti- PD-1 therapy to avoid unnecessary toxicities, and direct non-responders to alternative treatments. Such a pre- treatment or early on-treatment predictor would provide decision-enabling information to clinicians to optimize the treatment of melanoma patients. While there is enormous interest and intensive efforts from both academia and industry to identify predictors to response to ICI, the current biomarkers are suboptimal and early on- treatment biomarkers are not available for any cancer types. Exosomes are nano-sized vesicles secreted by cells to the extracellular milieu. We found that metastatic melanoma cells secrete exosomes enriched with PD- L1, which suppress the function of CD8+ T cells in circulation and facilitate tumor growth. In patients’ plasma, the level of circulating exosomal PD-L1 (“exPD-L1”) and its change during the course of anti-PD-1 treatment are associated with the patient response to anti-PD-1 therapy (Chen et al., Nature 2018). Most recently, we found that tumor associated macrophages (TAM) also secrete exosomes that carry PD-L1 (“TAM-exPD-L1”), which can be selectively and quantitatively measured in patient blood. TAM exosomes effectively suppress the proliferation and function of CD8 T cells. The overarching goals of Project 1 are to develop a quantitative liquid biopsy-based tool that enables clinicians to predict the patient response to ICI-based therapies, and to understand the role of TAM-derived exosomes in immune suppression. In Aim 1, we will test the hypothesis that exPD-L1, and especially TAM-exPD-L1, individually or in combination, are effective predictors of patient response to ICI. We perform the assays using a large multi-institutional validation set of patient samples across different major therapeutic contexts, taking advantage of the unique infrastructure SPORE offers. In Aim 2, we will systematically investigate the pivotal roles of TAM-derived exosomes in immune suppression using melanoma-macrophage co-culture system, humanized mouse system, and exosomes purified directly from patient tumor tissues. Together, our work will establish exosomal PD-L1 as a rationale-based clinically relevant stratifier that warrants future development for clinical diagnostics. The proposed study will also unveil a role of TAM exosomes in immune suppression, which will not only advance our understanding of immune suppression at new dimensions, but also helps develop novel therapeutic approaches to improve the treatment of patients with melanoma.