Thymic stromal lymphopoietin promotes interplay between breast tumor cells, neutrophils and Ly6Chi monocytes to regulate breast tumor progression

Abstract

Abstract Various human cancers display a T helper type 2 (Th2)-like inflammation. One possible mechanism suggested in human breast cancers is thymic stromal lymphopoietin (TSLP) secreted by breast tumor cells which can drive Th2 responses via tumor-associated dendritic cells. However, the interactions between TSLP, tumor cells, and other immune cells remain unclear. We found in breast tumor-bearing mice TSLP can also be produced by two pro-tumor myeloid cell populations, neutrophils and Ly6Chi monocytes. This non-tumor derived TSLP is crucial for both primary breast tumor growth and its metastasis to lungs. One important mechanism is myeloid derived TSLP can directly act on tumor cells and promote survival and TSLP production of tumor cells. Mice transplanted with TSLPR deficient breast tumor cells developed smaller primary breast tumors and fewer lung metastases. Conversely, mice that constitutively express TSLP in lungs transplanted with breast tumor cells had markedly increased lung metastases. Blocking TSLP in lungs resulted in a reduction in the number of lung metastases. We further discovered that TSLP signaling in Ly6Chi monocytes is crucial for their suppressor functions and their ability to differentiate into macrophages in tumors. Transfer of TSLP receptor deficient Ly6Chi monocytes significantly reduced lung metastases in tumor-bearing mice by changing T cell populations in lungs and in tumors. Our work is the first to show myeloid cell derived TSLP plays an important role in promoting breast tumor progression via maintaining tumor cell survival. We also provide a novel mechanism of the requirement of TSLP signaling in differentiation and suppressor functions in Ly6Chi monocytes.