Project Summary/Abstract Malignant tumors escape immune surveillance by evading, suppressing, or distorting immune function. The recent success of immune checkpoint blockade therapy relies on targeting suppressive mechanisms affecting effector function of cytotoxic T cells. However, the majority (60%) of patients with advanced melanoma fail to respond to immune checkpoint inhibitor (ICI) therapy, and many of those that do respond ultimately go on to develop resistance and disease progression. While the ability to promote immune responses to tumor has largely focused on tumor specific factors (e.g. tumor mutational burden), variability in the host immune repertoire may also explain the heterogeneity of responses seen from ICI treatment failure. ICI therapy works through multiple pathways to release the immunosuppressive brake on innate and adaptive immune cells. A very important mechanism of action of ICI is the targeting of inhibitory receptors on CD8+ T cells, which potentiates effector anti-tumor CD8+ T cell function. Although ICI can renew the effector function of CD8+ T cells, most patients with metastatic melanoma do not respond to checkpoint blockade due multiple mechanisms spanning both adaptive and innate immunity. A recently described cell population, innate lymphoid cells (ILCs), are present in secondary lymphoid organs, peripheral blood, and tissue, and have been described to modulate adaptive immune responses. Type 3 ILCs (ILC3s) can create immunosuppressive microenvironments through the secretion of Interleukin-17 (IL-17) leads to the recruitment of immunosuppressive cell populations and creation of an immunosuppressive microenvironment. ILC3s are the “first responders” to inflammation/tumor and dictate further innate and adaptive responses that may ultimately determine effectiveness of ICI therapy. However, the role of ILC3s in the mechanisms behind ICI failure and CD8+ T cell activation is currently not well understood. The ability to more specifically define the function of ILC3s in the melanoma tumor microenvironment (TME) has the potential to inform novel combination treatment strategies and dictate the downstream innate and adaptive cellular responses that drive ICI therapy effectiveness. However, this is currently not well understood.