Susanne Gabrielsson

Extracellular vesicles (EV), natural nanovesicles released by all cells, can activate or inhibit immune cells depending on their origin. Dendritic cell EVs can stimulate innate and adaptive immune responses and have been tested in humans as cancer immunotherapy, but require optimization. Conversely, cancer cell-derived EVs can inhibit immune responses, partly via checkpoint molecules such as PD-L1. They can also induce cancer cell proliferation and promote metastasis. Despite extensive research, the mechanisms for EV effects remain unclear. Leukotrienes (LT) are pro-inflammatory mediators, and we have discovered enzymes involved in LT synthesis in EVs.We hypothesize that manipulation of LTs and checkpoint molecules in EVs can increase their immunogenicity in immunotherapy. We will analyze immune responses and tumor growth in response to therapeutic EVs from cells, where these molecules are knocked out (KO) or overexpressed, in vitro and in vivo.We also hypothesize that the LT machinery in cancer EVs determines cancer cell behavior and immune cell activation. Wildtype (WT) or KO EVs will be added in vitro to cancer or immune cells and, proliferation, cell activation and differentiation will be analyzed. In vivo, WT or KO cells together with WT or KO EVs will be injected and cancer progression will be analyzed.This project will lead to a better understanding of EV-induced immune responses and potentially generate new targets and tools for the treatment of cancer.

Background: Sarcoidosis, chronic obstructive pulmonary disease (COPD) and asthma are debilitating and potentially fatal diseases. Diagnosis and monitoring now use invasive methods as in sarcoidosis, or are not satisfying when it comes to treatment guidance, and there is an unmet need for better diagnostic tools and treatments. Extracellular vesicles (EV) can stimulate or inhibit immune cells depending on their cell origin, and we believe that they both can help us understanding disease mechanisms and be useful as biomarkers. We have shown that EVs from patients with lung diseases display an altered protein- and RNA profile, and that they are pro-inflammatory. The high heterogeneity of EVs, and low sensitivity of current assays have been an obstacle in the field. We have developed novel multi parametric single EV assays, which are complementary for sensitivity, specificity and through-put. Objectives: We hypothesize that EVs are major players in lung diseases, and as such can be used as biomarkers and therapeutic targets. We aim to develop new diagnostic and prognostic tests for lung diseases based on EVs. By examining the function of subtypes of EVs we also aim to identify pathogenic EV subtypes that can function as novel therapeutic targets. Work Plan: We will analyze lung and plasma EVs for protein, RNA and metabolomics content from patients with sarcoidosis, COPD, asthma, as well as healthy smokers and non-smokers. Our partners have recently developed several single EV detection methods, but also for sorting of certain EV subtypes. The different single EV detection methods will be applied to detect rare individual EVs for biomarker development, and prototype tests will be developed. This will also give us leads for molecular mechanisms for how patients' EVs affect immune cells and epithelial cells. Functional experiments will be performed in vitro on blood cells and epithelial cells, and in vivo in zebrafish models. Candidate molecules will be blocked or overexpressed to verify the findings, and the data will be validated in larger patient cohorts. Significance: This work may lead to new treatment strategies for sarcoidosis, COPD and asthma, but also new diagnostic tests within 2-3 years. By revealing how EVs affect immune responses in these diseases, we can develop treatments that block or counteract disease promoting EVs. Depending on how easily target molecules on EVs are druggable, this could be implemented in the clinic in 5-10 years.

The body's own immune system can often kill single cancer cells that arise, but when cancer cells change rapidly, the immune system does not hang, and then the cancer cells can spread. Most cells in the body can release small bubbles of cell membranes, exosomes. Exosomes are found in body fluids, and exosomes can be produced in test tubes. Exosomes from immune cells can stimulate the cells that kill cancer cells. Conversely, cancer cells' exosomes can turn off an immune response, and we need to understand how this works to be able to use this in cancer treatment and to detect cancer. We want to understand how exosomes work, then modify exosomes molecularly so that they stimulate the immune system more. These are first tested in mice and then on human cells in test tubes, in order to finally be tested in humans. Cancer cells release exosomes that help spread the cancer. We will study exosomes from tumors, lymph nodes and urine from bladder cancer patients, to find molecules specific for the tumor or correlate with prognosis. We also want to study exosomes from lung cancer patients to understand their function and whether these can be used for early detection of cancer. This project aims to understand how exosomes affect the immune system. Then we can learn how they can be used to cure cancer by stimulating the patient's own immune system. Exosomes designed to be as immune stimulating as possible could be used in the treatment of several different cancers. Conversely, exosomes from cancer cells could be blocked to reduce the spread of cancer in the body. The project can also lead to better methods for diagnosing cancer.

The body's own immune system can often kill single cancer cells that arise, but when cancer cells change rapidly, the immune system does not hang, and then the cancer cells can spread. Most cells in the body can release small bubbles of cell membranes, exosomes. Exosomes are found in body fluids, and exosomes can be produced in test tubes. Exosomes from immune cells can stimulate the cells that kill cancer cells. Conversely, cancer cells' exosomes can turn off an immune response, and we need to understand how this works to be able to use this in cancer treatment and to detect cancer. We want to understand how exosomes work, then modify exosomes molecularly so that they stimulate the immune system more. These are first tested in mice and then on human cells in test tubes, in order to finally be tested in humans.   Cancer cells release exosomes that help spread the cancer. We will study exosomes from tumors, lymph nodes and urine from bladder cancer patients, to find molecules specific for the tumor or correlate with prognosis. We also want to study exosomes from lung cancer patients to understand their function and whether these can be used for early detection of cancer. This project aims to understand how exosomes affect the immune system. Then we can learn how they can be used to cure cancer by stimulating the patient's own immune system. Exosomes designed to be as immune stimulating as possible could be used in the treatment of several different cancers. Conversely, exosomes from cancer cells could be blocked to reduce the spread of cancer in the body. The project can also lead to better methods for diagnosing cancer.

The body's own immune system can often kill single cancer cells that arise, but when cancer cells change rapidly, the immune system does not hang, and then the cancer cells can spread. Most cells in the body can release small bubbles of cell membranes, exosomes. Exosomes are found in body fluids, and exosomes can be produced in test tubes. Exosomes from immune cells can stimulate the cells that kill cancer cells. Conversely, cancer cells' exosomes can turn off an immune response, and we need to understand how this works to be able to use this in cancer treatment and to detect cancer. We want to understand how exosomes work, then modify exosomes molecularly so that they stimulate the immune system more. These are first tested in mice and then on human cells in test tubes, in order to finally be tested in humans.   Cancer cells release exosomes that help spread the cancer. We will study exosomes from tumors, lymph nodes and urine from bladder cancer patients, to find molecules specific for the tumor or correlate with prognosis. We also want to study exosomes from lung cancer patients to understand their function and whether these can be used for early detection of cancer. This project aims to understand how exosomes affect the immune system. Then we can learn how they can be used to cure cancer by stimulating the patient's own immune system. Exosomes designed to be as immune stimulating as possible could be used in the treatment of several different cancers. Conversely, exosomes from cancer cells could be blocked to reduce the spread of cancer in the body. The project can also lead to better methods for diagnosing cancer.

The body's own immune system can often kill cancer cells that arise, but when cancer cells change rapidly, the immune system does not hang, and then the cancer cells can spread. Most cells in the body can release small bubbles of cell membranes, exosomes. Exosomes are body fluids, and exosomes can be produced in test tubes. Exosomer's role in the body is largely unexplored. If cancer-specific substances are on the surface of exosomes, they can stimulate immune cells that specifically kill cancer cells. Conversely, the cancer cells' exosomes can turn off an immune response, but we need to understand how this works to be able to use this in cancer treatment. Exosomes have begun to be tested against cancer in humans and the results show little side effects, but not as strong immune responses as desired. Therefore, we want to modify exosomes so that they stimulate the immune system more. Cancer cells release exosomes that can help spread the cancer. Our results also indicate that exosomes can spread signals for metastasis to adjacent cells. We want to find out the mechanisms for this, and investigate exosomes from patients to see if they can be used as a measure of cancer stage and prognosis. This project aims to understand how exosomes affect the immune system. Then we can learn how they can be used to cure cancer by stimulating the patient's own immune system. We also want to study if they can be used as an indicator of cancer or what stage the cancer is in. Exosomes designed to be as immune stimulating as possible could be used in the treatment of several different cancers. Exosomes from cancer cells could also be blocked to reduce the spread of cancer in the body, and also be used to diagnose cancer or if the cancer has metastasized.

The body's own immune system can often kill cancer cells that arise, but when cancer cells change rapidly, the immune system does not hang, and then the cancer cells can spread. Most cells in the body can release small bubbles of cell membranes, exosomes. Exosomes are body fluids, and exosomes can be produced in test tubes. Exosomer's role in the body is largely unexplored. If cancer-specific substances are on the surface of exosomes, they can stimulate immune cells that specifically kill cancer cells. Conversely, the cancer cells' exosomes can turn off an immune response, but we need to understand how this works to be able to use this in cancer treatment. Exosomes have begun to be tested against cancer in humans and the results show little side effects, but not as strong immune responses as desired. Therefore, we want to modify exosomes so that they stimulate the immune system more. Cancer cells release exosomes that can help spread the cancer. Our results also indicate that exosomes can spread signals for metastasis to adjacent cells. We want to find out the mechanisms for this, and investigate exosomes from patients to see if they can be used as a measure of cancer stage and prognosis. This project aims to understand how exosomes affect the immune system. Then we can learn how they can be used to cure cancer by stimulating the patient's own immune system. We also want to study if they can be used as an indicator of cancer or what stage the cancer is in. Exosomes designed to be as immune stimulating as possible could be used in the treatment of several different cancers. Exosomes from cancer cells could also be blocked to reduce the spread of cancer in the body, and also be used to diagnose cancer or if the cancer has metastasized.