Friday, May 16, 2025
5/16/2025
Targeting heat shock factor 1 (HSF1) to increase tumor infiltrating lymphocytes in metastatic breast cancer. - ABSTRACT. Metastasis is the primary cause of breast cancer deaths and many therapies for metastatic patients are more effective when immune cells are within the tumor. However, metastatic breast tumors have less immune cells compared to primary tumors, especially CD8+ T cells, whose absence is a predictor for worse outcomes. This creates a problem wherein tumors exclude antitumor immune cells that would make therapies more effective. A gap in knowledge is the regulation of immune cell infiltration to metastatic tumors, which could be harnessed to increase immune trafficking to make therapies more effective. Our work identified that heat shock factor 1 (HSF1) can suppress the presence of CD8+ T cells in primary breast tumors. This relationship was confirmed in vivo as HSF1 loss reduced tumor volume and evoked an influx of CD8+ T cells and myeloid cells. Depletion of CD8+ T cells rescued tumor growth with HSF1 knockdown suggesting HSF1 protects breast tumors from immune-mediated killing. Attraction of CD8+ T cells with HSF1 knockdown was regulated by suppression of CCL5, a chemokine for CD8+ T cells. Our preliminary studies also showed HSF1 has increased activity in matched metastatic tumors compared to primary tumors and HSF1 activity was negatively correlated with CD8+ T cells in primary and metastatic human tumors. We hypothesize that HSF1 activity in metastatic breast tumors reduces attraction of CD8+ T cells, leading to decreased levels of other antitumor immune cells, thereby making metastatic tumors less responsive to treatments. To test this hypothesis, we propose three aims. Aim 1: Determine the role of HSF1 in the recruitment of immune cells to metastatic breast tumors. We will utilize an inducible system to knockdown or overexpress HSF1 in immune-competent mouse models and perform single cell RNA sequencing to identify changes in cell populations. We will correlate active HSF1 in human primary and metastatic tumors using multiplex tissue immune phenotyping. We will also determine the importance of CD8+ T cells to metastatic tumor growth and the importance of CCL5. Aim 2: Assess the efficacy of HSF1 inhibition on metastatic tumor response to chemotherapy and immune checkpoint therapy. We will utilize immune competent models to genetically reduce HSF1 or two HSF1 small molecule inhibitors (SISU- 102 & NXP800) with therapies that benefit from an influx of immune cells (paclitaxel, capecitabine, anti-PD-L1). Aim 3: Determine the role of HSF1-regulated myeloid cell populations in breast tumors. We will determine which immune populations are dependent on CD8+ T cells and IFN-γ for the influx into HSF1-depleted tumors, whether CD8+ T cells primed from HSF1-depleted tumors adoptively transfer anti-tumor immunity, and the effect of myeloid cells from HSF1-depleted tumors on CD8+ T cell and cancer cells. These studies will have a significant impact in metastatic breast cancer with a greater understanding of metastatic tumor-immune interactions and potentially develop a therapeutic strategy to enhance the efficacy of therapies for this patient population that would decrease mortality and extend the lives of these vulnerable patients.
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