Intratumoral Steroid Production as a Mechanism of Immune Evasion in Adrenocortical Carcinoma (ACC)
Abstract
Fiscal Year 2018 Peer Reviewed Cancer Research Program Section II.A.1. Topic Area – Adrenal Cancer, Immunotherapy. The adrenal glands are located above each kidney and produce a diverse array of hormones (including steroids like cortisol) essential for life. Adrenal cancer (adrenocortical carcinoma, [ACC]) is an extremely rare cancer of these glands but is frequently aggressive and routinely fatal. Surgery is the only treatment with the potential to cure ACC. However, if the disease spreads to other organs (called metastasis), curative surgery is no longer possible. Unfortunately, approximately 50% of patients with ACC already have metastases at diagnosis, and up to 70% of patients who are declared cancer-free after surgery relapse with metastases. The treatments for patients with metastatic ACC include intravenous chemotherapy and an oral medication derived from the insecticide DDT and often cause debilitating side effects. Unfortunately, <10% of patients who receive this care will survive for 5 years after developing metastatic ACC. New treatments for metastatic ACC are urgently needed. A patients immune system is the first line of defense against infections and cancer. Often, cancer cells can grow in the body because they have developed mechanisms to hide from the immune system. In recent years, scientists have developed therapies that unmask cancer cells and expose them to the immune system, called immunotherapy. Once a cancer patient has been treated with immunotherapy, their immune system will begin to fight the cancer in the same way it fights an infection. Immunotherapy has grown popular because it has cured patients with otherwise devastating cancers like metastatic melanoma and lung cancer, and it causes significantly fewer side effects than conventional chemotherapy. Indeed, immunotherapy was recently approved by the Food and Drug Administration for a variety cancers, including a very rare type of ACC. However, immunotherapy does not always work, and scientists are still trying to understand what biological factors determine therapy success. One of such factors is the number of immune cells inside a tumor – the more immune cells there are, the more likely immunotherapy will work. Our group has recently performed a comprehensive study on ACC and identified that immune cells are virtually absent in two-thirds of ACC tumors. Unfortunately, patients with this type of ACC have the most aggressive and deadly disease, and immunotherapy may not be an effective treatment. Interestingly, these ACC tumors produce a high amount of cortisol and other steroids in an uncontrolled manner; high levels of cortisol are known to weaken the immune system. Our hypothesis is that uncontrolled steroid production acts as a protective shield for ACC against the immune system, preventing immune cells from penetrating the tumor. We predict that decreasing steroid production with special types of medications would increase the number of immune cells in ACC tumors, and therefore the number of patients with ACC who may respond to immunotherapy. The goal of our proposal is to understand if blocking steroid production in tumor cells can enable the immune system to fight ACC. First, we will study a large collection of ACC samples to characterize which steroid hormones (among 25 types) are produced by ACC cells, and identify which immune cells are present in ACC tumors that do not produce steroids. We will then perform experiments with ACC cells and immune cells in a dish to study whether steroids produced by ACC affect immune cell function. Finally, we will use a mouse model of ACC to test if decreasing steroid production with pharmaceutical agents can potentiate the effects of immunotherapy, and cure ACC in the mouse. During this 2-year award period, our studies will characterize a possible novel mechanism by which ACC escapes the immune system and will help physicians develop novel strategies to improve outcomes of immunotherapy an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910623
Entities
People
- Gary D. Hammer
Organizations
- United States Army
- University of Michigan