The Immunologic Role of miR-21 in the Prostate Cancer Tumor Microenvironment
Abstract
Prostate Cancer (PCa) is the second leading cause of male cancer death in America. Prostate tumors are known to have low numbers of cancer-killing immune cells within the tumor microenvironment (TME) and low antitumor cytokine signaling. This unique TME has limited the efficacy of current immunotherapies for PCa patients. It is not fully known why prostate tumors exhibit such low anti-tumor immunity. However, it is widely believed that PCa responses would be improved if drugs could be developed to alter the tumor immune microenvironment. This idea development grant focuses on one gene, called miR-21, as a key regulator of the prostate tumor immune microenvironment and as a therapeutic target for prostate tumor immune modification. miR-21 belongs to a class of genes called microRNAs (miRNAs). Of all the miRNAs, miR-21 is the most commonly overexpressed in human cancer. Studies by our laboratory and others have strongly linked miR-21 to PCa development, progression, and therapeutic resistance. Interestingly, miR-21 levels appear to increase in many different cell types within a tumor, including cancer cells, immune cells, and stromal cells. To study the biology of miR-21 in PCa, we developed a mouse model where the miR-21 gene has been genetically knocked out (deleted/removed) from all cell types. This includes prostate cells, prostate cancer cells, stromal cells, and immune cells. We then bred these mice with Hi-Myc mice, which are designed to develop PCa in a way that is very similar to human disease. Importantly, we found that miR-21 KO mice had much smaller tumors than normal Hi-Myc mice. More interestingly, we found the immune signaling to be markedly different in the prostate tumors of miR-21 KO mice. In light of our findings, we now hypothesize that miR-21 contributes to the development and maintenance of the prostate tumor immune microenvironment, cytokine signaling, and immunotherapeutic resistance. Below we propose two specific aims to delineate the role of miR-21 in prostate tumor immunology and investigate its potential as a therapeutic target. Hypothesis: Elevated miR-21 expression contributes to development and maintenance of the prostate tumor immune microenvironment, cytokine signaling, and immunotherapeutic resistance. Specific Aims: Aim 1. Delineate the role of miR-21 in the development of the immunosuppressive TME using a novel Hi-Myc/miR-21 KO mouse model. The molecular underpinnings of the prostate tumor immune microenvironment remain incompletely understood. Our preliminary data implicate miR-21 as a driving factor in the development of prostate tumor immune biology. Herein, we propose to compare the immune cell infiltrate of prostate tumors developed in miR-21 WT (wild type/normal) and miR-21 KO mice by a cutting edge strategy called single-cell RNA sequencing. This technique provides detailed information about all of the different immune cell types in a tumor and their activity (anti-tumor or anti-immune). We will use this data and other standard techniques to characterize the pathways and cell types regulated by miR-21 during PCa development. We will compare these pathways from mice to human PCa by applying bioinformatic analyses to gene expression databases. Aim 2. Determine the role of miR-21 in prostate tumor immunology and sensitivity to immune checkpoint inhibition using an autochthonous MyC-CaP tumor model in miR-21 WT and mIR-21 KO mice. Our preliminary studies implicate a role for miR-21 in tumor immunology and immune checkpoint signaling. Herein, we propose to develop a new system to compare the immune cell infiltrate and cytokine profiles of PCa by growing mouse PCa tumors under the skin (subcutaneous) of miR-21 WT and miR-21 KO mice. This model will allow us to measure tumor growth in real time, study immune cells that enter the tumor, directly treat tumors, and measure their therapeutic response. We will compare the efficacy of immune checkpoint therap
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910450
Entities
People
- Shawn E Lupold
Organizations
- Johns Hopkins University
- United States Army