Commensal Bacteria with High Homology to Nonmutated Tumor Antigens May Prevent Clinically Effective Vaccination in Breast Cancer
Abstract
This proposal addresses two overarching challenges: (1) eliminating the mortality associated with metastatic breast cancer and (2) revolutionizing treatment regimens to be more effective, less toxic, and impact survival. Immunotherapy is now becoming a standard of care for many cancers. Immune checkpoint inhibitor monoclonal antibodies take advantage of a patient’s own immune response against their tumors and augment that response to control tumor growth or in some cases even cure cancer. The cancer types where these agents are most effective are those that already have a Type I immune response present in their tumors. Type I T-cells are CD4 T cells that secrete substances that generate tissue-destructive inflammation and support the development of cytotoxic T-cells (CTL) that can directly kill the tumor. In metastatic melanoma and non-small cell lung cancer, use of these drugs has resulted in significant clinical responses, including complete responses. Immunotherapy is now standard of care for the treatment of metastatic melanoma and non-small cell lung cancer. These results have not been able to be translated to metastatic breast cancer. The type of immune response that dominates in breast cancer is not Type I immunity, which we know could be therapeutically effective, but rather Type II immune responses. In breast cancer, CD4 T-cells secrete IL-10 and IL-4, i.e., Th2 T-cells, which support the generation of antibodies, but also serve to limit the development of CTL. Type I T-cells are either not found at all or found at low levels in the tumors of patients with breast cancer. Immune-based strategies that can effectively generate tumor-specific Type I immunity in breast cancer patients are needed to control tumor growth and synergize with other forms of immunotherapy such as immune checkpoint inhibitors. We have made a novel finding that identifies a significant barrier to the generation of Type I T-cells in breast cancer patients. We discovered that many common immunogenic proteins expressed by breast cancer cells share a high degree of homology to microbial species found in the human gut microbiome. High levels of Type II T-cells specific for both microbial antigens and tumor antigens can even be found in women who do not have cancer. We think this high level of cross-reactive Th2 will prevent the development of Th1 and CTL directed against breast cancer. If this existing Th2-cell memory population can be diminished in some way, Type I immune responses elicited by vaccines or other modalities can more readily synergize with immune checkpoint inhibitor drugs to enhance therapeutic efficacy in breast cancer significantly limiting the mortality and morbidity associated with this stage of the disease. In this proposal, we will first generate cross-reactive microbial antigen-tumor antigen T-cells and assess whether those cells traffic to the tumor and negatively modulate the tumor microenvironment. We will next study the effect of vaccination in germ-free mice, who don’t have a microbiome, to determine whether vaccines that were previously not effective because of Th2 limiting the immune response, now become effective. Finally, we have identified microbes that are not associated with any homologies to self-tumor antigens. We will feed mice these microbes to alter their gut microbiome to see if we can limit or even eliminate the chronic stimulation of the microbial antigen-tumor antigen cross-reactive Th2 population. If these cells can diminish in number, perhaps more clinically effective immunity will be able to develop. If these experiments are successful, our next step would be to test whether the concept works in metastatic breast cancer patients by modulating the gut microbiome to reduce these suppressive cells. Immunotherapy has made a tremendous difference in the survival outcomes of patients with metastatic melanoma and lung cancer. We wish that extended survival for our patients with met
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810087
Entities
People
- Mary Disis
Organizations
- United States Army
- University of Washington