Executive Summary : | Triple-negative breast cancer (TNBC) is the most aggressive among all other cancer subtypes with more recurrence cases. It is now well-accepted that the immune system plays a key role in TME. The immune suppressor cells such as TAMs, Tregs, MDsCs, and their crosstalk enhance tumor progression by suppressing the immune microenvironment. In spite of the advances in therapeutic approaches, drug resistance, and disease relapse are still challenges for clinical and translational studies in TNBC. To address these challenges, we will explore the role of TAM-Tregs crosstalk in disease relapse. studies have shown that TAMs recruit Tregs by secreting various anti-inflammatory cytokines such as IL-4, IL-13 IL-10, TGF-beta which in turn enhances the TAM polarization. The role of the positive feedback loop in disease recurrence is not well understood yet. We will establish the role of TAM-Treg crosstalk in disease relapse. Moreover, metabolism plays a very important role in the functioning of different subtypes of immune cells. Whereas, in M1 arginine breaks into nitric oxide by iNOs, in M2 arginine breaks into ornithine and urea by Arginase-1. Ornithine, produced in arginine metabolism, is directed into downstream pathways of polyamine and proline synthesis, the byproducts are necessary for cell proliferation, tissue remodeling, and collagen synthesis in cancer. Moreover, higher expression of ARG-1 decreases the extracellular level of arginine which impairs the proper T cell functioning in TME. Thereby, ARG-1 could be proven as a novel target to deregulate the TAM-Tregs crosstalk in disease relapse. We will isolate the CsCs, TAM, Tregs, and fibroblasts to form spheroid, and by ARG-1 knocked down, we will study the role of ARG-1 in TAM-Treg crosstalk in TNBC TME. By knocking down ARG-1, we will study the role of TAM-Tregs crosstalk in the recurrence of TNBC. Elucidating the role of ARG-1 in TAM-Treg crosstalk in recurrence will give a novel therapeutic target for the disease-free survival of TNBC. Additionally, this could be used as personalized immune therapy in recurrent TNBC. |