Abstract A17: Modulation of tumor-associated macrophages towards an antitumor phenotype

Abstract

Abstract An effective anti-tumor immune response is a potentially powerful tool to be deployed against cancer. While the concept of manipulating the immune system to attack cancer cells has been pursued for nearly a century, the main focus has been on manipulating the adaptive immune system, primarily T-cells. While this approach has recently been met with some significant successes, 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 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 tumor cells to apoptotic signaling, and in doing so, affect 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 conditioned media (CM) from M1 macrophages “primes” tumor cells, which correlates to their increased chemosensitivity. Interestingly, we have found some tumor cells to be resistant to CM from M1 macrophages. We have performed gene expression analysis on these two phenotypes of tumor cells, to uncover why some, but not others, are sensitive to M1 macrophages. We are working to validate these findings, as it will be important to know who will benefit from TAM modulation clinically. Additionally, we are working with a novel compound that we have shown modulates TAMs to an anti-tumor phenotype in vivo and induces rapid tumor regression in an immunocompetent mouse model of breast cancer. These results suggest modulating TAMs towards an anti-tumor phenotype may have great promise for cancer therapy. Finally, we are investigating strategies to convert M2 TAMs to a M1 phenotype. We have initiated 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 tumor-associated macrophages towards an antitumor phenotype. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A17. doi:10.1158/1538-7445.CHTME14-A17