# Mechanisms of Exosome Driven Immunoregulation of Cancer Progression

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $155,680

## Abstract

PROJECT ABSTRACT:
Antibodies against the immune checkpoint proteins PD-L1 and PD-1 have revolutionized cancer therapeutics
resulting in durable remissions in many patients previous considered incurable. However, a majority of patients
remain resistant and cancer types can vary greatly in their response rates. Thus, there is an urgent need to
understand the variation in response in order to improve cancer care. This proposal brings together a team of
investigators with complementary expertise in basic, translational, and clinical science who share the long-term
goal of finding novel approaches to categorize and personalize cancer treatments. Recent results from the
investigators suggest a major role for the packaging of immune checkpoint proteins in exosomes underlying the
variation in responses to immune checkpoint inhibitors among patients. Specifically, varying amounts of PD-L1
can be trafficked to exosomes, which in turn can act at a distance to suppress anti-tumor T cell function, enabling
tumor progression, even in models resistant to anti-PD-L1 treatments. The objective of this proposal is to build
on these findings by focusing on the mechanism of exosomal PD-L1 packaging, action, and resistance to
therapeutic antibodies. In particular, the proposal will test the overall hypothesis that tumor cells can selectively
package PD-L1 into exosomes that suppress T cell priming at distal sights in a fashion that is distinct from the
cell-cell interactions of PD-L1 and PD-1 normally seen in the tumor bed. The hypothesis is premised on extensive
preliminary data using in vitro and in vivo models showing that the relative fraction of PD-L1 packaged in
exosomes versus retained in cells varies between cell lines, that suppression of exosomal PD-L1 can result in
long-term systemic anti-tumor immunity, and that exosomal PD-L1 is resistant to anti-PD-L1 antibodies. To test
the overall hypothesis, the following aims are proposed: 1) Uncover mechanisms underlying the selective
packaging of PD-L1 into exosomes, 2) Evaluate the mechanistic basis of exosomal PD-L1’s impact on systemic
immunity, 3) Dissect how exosomal PD-L1 interacts with and regulates its target cells. In aim 1, structure/function
and proteomic approaches are proposed to identify the regulators of PD-L1 packaging into exosomes.
Furthermore, associations between expression of these factors and resistance to therapy will be evaluated using
primary patient samples. In aim 2, mouse-based immunological approaches and patient samples will be used to
determine where in the immune axis exosomal PD-L1 functions. Uncovered insights will then be used to develop
a novel therapeutic approach to enhance the anti-tumor immune response. In aim 3, microscopy and functional
studies in in vitro models along with association studies with patient samples will be used to determine how
exosomal PD-L1 interacts with its target cells potentially explaining its resistance to antibodies. The proposal is
highly significa...

## Key facts

- **NIH application ID:** 10381379
- **Project number:** 3U01CA244452-01S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Robert Blelloch
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $155,680
- **Award type:** 3
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10381379

## Citation

> US National Institutes of Health, RePORTER application 10381379, Mechanisms of Exosome Driven Immunoregulation of Cancer Progression (3U01CA244452-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10381379. Licensed CC0.

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