Characterization of the Tumor Microenvironment to Build Novel Strategies for Prevention and Treatment of Cancer
Abstract
Background: Our results and publications provide strong evidence that levels of a virus present in the DNA of all humans are much higher in breast cancer (BC) patients than in persons without cancer. This virus is called human endogenous retrovirus type K (HERV-K), and its expression leads to BC onset and contributes to BC progression. Significantly reduced tumor growth, and importantly prevention of metastasis, was demonstrated by our lab after targeting HERV-K with various therapies that knock down the levels of this virus in BC cells. Furthermore, HERV-K specific T cells have been demonstrated to trigger an antigen-specific immune response in BC. If these T cells can enter the tumor, they would kill the BC cells in the tumor. Recently, we discovered that HERV-K is overexpressed in drug-resistant BC cells. Cumulatively, our data show that HERV-K is impacting a number of pathways in the BC cell that impinge on drug resistance, the tumor microenvironment (TME), and therapy efficacy, all of which are important to BC patient survival. Overarching Challenges: (1) Identify what drives breast cancer growth; determine how to stop it. (2) Eliminate the mortality associated with metastatic breast cancer. Objective/Hypothesis: Our hypothesis is that HERV-K is a potential immunotherapy target for preventing both metastasis and development of drug resistance, a major problem in BC. Also, we hypothesize that increased expression of HERV-K may make BC cells with drug resistance vulnerable to immunotherapy that targets HERV-K. We propose to investigate whether HERV-K is an immunotherapeutic target in drug-resistant BC cells, especially in combination with checkpoint blockade therapies (CBT), which have shown only limited success in BC patients. These studies have a strong potential to transfer to the clinic. Specific Aims: (1) To identify key molecular networks and signaling pathways common to HERV-K expressing drug-resistant BC. (2) To determine whether immunotherapy will increase tumor-infiltrating lymphocytes (TILs) and immune response to effectively convert “cold” into “hot” drug-resistant breast tumors. (3) To determine synergistic effects of immunotherapy combined with CBT. (4) To characterize immune profiles and determine heterogeneity within TME at a single cell level. Study Design: We will carry out experiments on a panel of drug-resistant BC cells with different metastatic potential, with or without HERV-K knockdown or overexpression, and analyze how they become resistant to chemotherapy. We will evaluate the effectiveness of HERV-K specific T cells or CAR T cells in killing chemotherapy resistant BC cells that overexpress HERV-K. CAR T cells are specialized T cells that home in on the HERV-K targets on BC cells and lyse the tumor cells. We will determine (1) whether HERV-K triggers an immune response and importantly whether it can effectively convert BC from “cold” into “hot” if it combines with the correct CBT partner(s) and (2) whether the killing by K-CAR T cells is enhanced. CBT prevents exhaustion of the T cells inside the tumor. We will examine if HERV-K tumor cell expression can directly and indirectly influence immune cell groups that are helpful or harmful for BC patients, first in the lab and then in animal models. We will take multiple innovative approaches using HERV-K vaccines, targeting antibodies and HERV-K specific CAR-T cell therapy alone, or combined with CBTs, chemotherapeutic agents, and chemotherapy dosing. Finally, single cells from fresh tumor tissues will be labeled with 10X barcodes for identification and used to generate cDNA. This simultaneous examination of TME cell gene expression with matched, full-length, paired clonotype sequence information at a single cell level will provide new insights into tumor immunology. Impact: We are proposing to use HERV-K as a BC-specific target to develop immunotherapy against BC, which is aimed at preventing immunosuppression
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010376
Entities
People
- Feng Wang-johanning
Organizations
- United States Army