Overcoming stress driven suppression of the anti-tumor immune response in cancer - understanding the MDSC piece of the puzzle

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SUMMARY: Chronic stress can suppress immunity. However, details about how stress affects tumor growth and anti-tumor immunity are still missing or poorly understood. Myeloid derived suppresser cells (MDSCs) are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in tumor growth, differentiation and metastasis. Exactly how stress, particularly adrenergic stress, affects MDSCs is largely unknown. Addressing this piece of the puzzle is the overall goal of this application. The hypothesis of this proposal is that increased level of norepinephrine during chronic stress activates β- adrenergic receptor (β- AR) signaling in MDSCs and increases pro-tumor functions and survival of MDSCs, both in the primary tumor microenvironment and in metastatic sites (lung and bone marrow). We will address this hypothesis in two specific aims: Aim 1: To test the hypothesis that β2-AR signaling regulates MDSC distribution, accumulation and function in tumors and Aim 2: To determine mechanisms by which β2-AR signaling alters MDSC survival in the tumor. We will use metastatic 4T1 and non-metastatic AT-3 murine breast cancer models. 4T1 is a clinically relevant model of breast cancer that is implanted orthotopically in the mammary gland and metastasizes to the lung, as well as other sites and is known to induce MDSC accumulation. AT-3 tumor cell line was established from a primary mammary gland carcinoma of an MMTV-PyMT transgenic mouse model and induces CD11b+Gr-1+ MDSC response after implantation. We will use three different strategies to reduce and/or block adrenergic signaling. These approaches include genetic (β2AR-/- mice compared to littermate wild-type controls), pharmaceutical (beta-AR blockers compared to PBS) and physiological (cold housing versus warm housing). Altogether, my proposed research will provide an important research experience that will reveal the key role of β2-adrenrgic signaling in tumor growth in general, and immune-inhibitory functions of MDSCs in particular, and reveal new mechanisms by which chronic stress promotes tumor growth. This Training Grant will enhance my ability to experience many other critical career-building opportunities that will greatly increase my chances of obtaining a K99/R00 award and my own independent laboratory in the future. It can also help me to take advantage of opportunities to learn new techniques in complimentary fields, such as genomic applications, which will expand my expertise and independence.