While several avenues of manipulating the adaptive immune response have met with striking clinical success in recent years, there is also a growing appreciation of the innate immune system in mediating tumor reduction and elimination. In fact, tumor associated macrophages (TAMs) are the most abundant immune population in a breast tumor. Although M1 macrophages have potent anti-tumor activity, TAMs are phenotypically polarized to M2 macrophages, which support tumors. Clinically, a high tumor density of TAMs has been associated with chemoresistance and a worse clinical outcome. Using a tool, BH3 profiling, that is unique to the Letai Laboratory, we have identified that macrophage phenotype can alter the sensitivity of neighboring tumor cells to apoptotic signaling, and enhance their response to chemotherapy.
The Letai Laboratory has developed a unique and novel assay to predict a cancer cell's response to chemotherapy called BH3 profiling. BH3 profiling is used to determine whether a cell is relatively close to the threshold of apoptosis (“primed” for death), or relatively far from the threshold (“unprimed”). We have found that the priming of cancer cells, as measured by BH3 profiling, is by itself a predictor of clinical response to conventional chemotherapy. Using the BH3 profiling strategy, we show for the first time that M1 macrophages “prime” breast tumor cells for apoptosis, which correlates to their increased chemosensitivity. Interestingly, we have found some breast tumor cells to be resistant to M1 macrophage induced priming. We have performed gene expression analysis on these two phenotypes of breast tumor cells, to uncover why some, but not others, are sensitive to M1 macrophages. We also have identified how M1 macrophages increase the priming of tumor cells, making them more chemosensitive. These results suggest modulating TAMs towards an anti-tumor phenotype may have great promise for cancer therapy. To this end, we are investigating strategies to convert M2 TAMs to a M1 phenotype. We have conducted a high throughput screen (HTS) at the Institute of Chemistry and Cell Biology (ICCB) – Longwood, at Harvard Medical School, to identify small molecules that polarize macrophages to an anti-tumor phenotype. We have identified several interesting small molecules and are working to validate their clinical significance.
Citation Format: Jennifer L. Guerriero, Anthony Letai. Modulation of macrophages in breast tumors towards an anti-tumor phenotype. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A71.
- ©2015 American Association for Cancer Research.