Jennifer Guerriero, PhD
Instructor in Medicine
Head Scientist Team Macrophages
While the immune system is perhaps best known for its ability to fight off infections, there is increasing evidence that the immune system can participate in combating cancer as well. Immune cells such as tumor associated macrophages (TAMs) can represent up to 50% of a breast tumor mass. Macrophages can broadly be divided into two types: M1 (anti-tumor) and M2 (pro-tumor) macrophages. TAMs generally have M2 properties and promote tumor progression, metastasis, and resistance to chemotherapy. Clinically, a high tumor density of TAMs has been significantly associated with resistance to chemotherapy and a worse clinical outcome of human tumors. Recently, pharmaceutical compounds have been developed to target the pro-tumor effect of TAMs. These compounds have had a variety of effects including changing TAMs to M1 macrophages. A complete understand of how M1 macrophages can influence cancer cell death is lacking. Therefore, here, we propose to study the biology and mechanisms of how M1 macrophages affect tumor breast tumor cells, using a novel assay developed in the Letai laboratory called BH3 profiling. BH3 profiling is used to determine whether a cell is close to the threshold of cell death (relatively "primed" for death), or relatively far from the threshold ("unprimed"). Using BH3 profiling, we have identified that M1 macrophages can alter the sensitivity of breast tumor cells to cell death signaling, and in doing so, sensitize these tumor cells to chemotherapy. However, we also found that some breast tumor cells are not affected by M1 macrophages. We are working to understand why some breast tumors, but not others are sensitive to M1 macrophages, as it will be important to know which cancer patients may benefit from macrophage modulation during cancer therapy.
Additionally, we are working with a pharmaceutical company who has developed a novel, first in class compound which polarizes macrophages to a M1 phenotype. We have shown that although this compound has no direct anti-tumor properties, it mediates tumor regression in a mouse model of breast cancer. We are working with the pharmaceutical company as part of a sponsored research agreement to move this compound into Phase I Clinical Trials.
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