Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with dismal clinical outcome. Immune checkpoint blockade (ICB), which blocks inhibitory pathways on T cells, has surged to the forefront of cancer therapy with clinical success in a variety of cancer types. However, ICB for TNBC only benefits 10-20% of patients. Thus, a deeper understanding of the immune landscape in TNBC is required to develop efficacious therapies and delineate prognostic biomarkers of disease.
We have developed combination therapy platforms that sensitize TNBC tumors to ICB. Using a clinical chemotherapy (FEC) combined with oncolytic virotherapy (oHSV-1) we show enhanced tumor-infiltrating lymphocytes (TILs), upregulation of B cell receptor signaling pathways, suppression of myeloid-derived suppressor cells (MDSCs) and improved survival. In vivo depletion studies revealed that B cells were required to achieve cures with treatment. Furthermore, the absence of B cells resulted in the expansion of MDSCs. This crucial finding of the importance of B cells for mediation and downregulation of MDSCs is a novel and significant contribution to the field.
RNA sequencing revealed that two of the top upregulated genes in mice treated with FEC + oHSV-1 were S100A8 and S100A9, calcium binding proteins highly expressed in myeloid cells. These genes have controversial findings in the literature with both pro- and antitumorigenic functions being reported. Investigation of data from the Cancer Genome Atlas revealed that high levels of S100A8 and S100A9 correlate with improved prognostic outcomes in breast cancer patients. In line with the clinical data, our data suggests that increased levels of S100A8 and S100A9 results in improved responses to immunotherapy treatments and that this increased expression is involved in macrophage-mediated epigenetic reprogramming of the tumor microenvironment.
Our second therapeutic platform used a radiolabeled biomolecule containing the beta-emitting radioisotope, lutetium-177. We found that two doses of radiotherapy, combined with ICB improved overall survival in murine TNBC tumors, increased TILs and suppressed circulating MDSCs. These findings offer insight into the newly explored field of combination radioimmunotherapy and again highlight the importance of suppressing MDSCs to alleviate tumor immunosuppression. / Thesis / Doctor of Philosophy (PhD) / Triple-negative breast cancer (TNBC) has poor prognostic outcomes due to lack of expression of targets for therapy. As such, patients routinely undergo aggressive treatment regimens with many harsh side effects, including high levels of toxicity. Immunotherapy, a form of therapy that boosts the immune system to fight cancer cells, has gained increasing prominence largely due to its safety and low toxicity to the patient. In the work within this dissertation, we have developed therapeutic platforms and studied them in a murine model of TNBC. The completed studies show the use of clinical therapies, in combination with immunotherapy and investigate the fundamental biology associated with therapeutic outcomes. These findings contribute knowledge to progress clinical regimens for TNBC patients as well as to better identify patients that will respond to therapy. Although this proposal is specific to breast cancer, the underlying concepts can be applied to many other forms of cancer.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26305 |
| Date | January 2021 |
| Creators | Vito, Alyssa |
| Contributors | Mossman, Karen, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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