Exploring the effect of arginine starvation on autophagy and type I IFN response in cancer cells
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Female breast cancer is now estimated to be the most diagnosed cancer, accounting for 11.7% of all cancer cases worldwide. Tumors are heterogenous tissues consisting of various types of cells together creating the tumor microenvironment (TME) and can be classified as immunologically “hot” or “cold”, depending on their level of T-cell infiltration. A cold tumor has a low level of T-cell infiltration and is correlated to poor prognosis. Cancer cells can alter the TME by many mechanisms, one being altering their metabolism and recruiting immunosuppressive cells, such as myeloid derived suppressor cells (MDSCs) or neutrophil like cells which can secrete arginase-1 (ARG1). By reducing the abundance of arginine, ARG1 suppresses the activity of effector T-cells, resulting in a cold tumor. Arginine, which is an essential amino acid for many cancer cells, can bind to CASTOR, a negative regulator of mammalian target of rapamycin (mTORC1), resulting in activation of mTORC1, which in turn suppresses autophagy. This mechanism suggests that when arginine is absent, mTORC1 is inhibited, and autophagy can be initiated. Autophagy has been demonstrated to suppress the type I IFN response, suggesting that autophagy, induced by arginine starvation, could suppress type I IFN response and contribute to an immunologically cold tumor. Hence, it is of great interest to explore the mechanisms by which arginine starvation affects the type I IFN response in cancer cells, and if it is possible to turn a cold tumor into a hot tumor and thereby improve the prognosis of cancer patients. In this thesis, four different human breast cancer cell lines divided into pairs of non-invasive and invasive cells were utilized. We found that the invasive cell lines have a constitutive type I IFN response in culture, which is not observed in their non-invasive counterpart. Arginine starvation dampened the type I IFN response in the invasive cells. We further observed that although the basal level of autophagic proteins was higher in the invasive cell lines, the non-invasive cells had a higher autophagic flux. We also found that arginine starvation induced autophagy in the non-invasive cells. Interestingly, inhibition of autophagy caused ejection of p62, and pTBK1, and in small amounts STING, into the growth medium in the invasive cells, suggesting they might be in a complex which is ejected as a survival mechanism when the autophagic degradation is compromised.
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