Immune checkpoint inhibitors (ICIs) are a prominent type of immunotherapy used in the treatment of patients with triple negative breast cancer (TNBC) and other cancer types. ICIs block negative regulators of CD8+ cytotoxic T cell activity to sustain their antitumor potency.
One such example is anti-PD-1 antibody, an ICI that binds to the inhibitory receptor PD-1 on the surface of these CD8+ T cells. Blocking PD-1 signaling, in turn, prolongs CD8+ T responses, which has led to improved survival outcomes across multiple solid cancer types, including TNBC.
However, across those same cancer types, ICIs have achieved modest benefits over standard-of-care treatment or are effective in only subsets of patients. Therefore, while ICIs are promising, there are multiple barriers within the TME that potentially limit their efficacy. Our laboratory focuses on the unique roles and actions of infiltrating, tumor-supportive myeloid populations.
Populations of blood cells, known as T-lymphocytes (which include both CD4+ and CD8+ T cell subsets) are critical for host defense against disease, including cancer. The CD8+ T cell subset has the capacity to bind to and directly kill cancer cells, and this occurs through multiple steps simplified here. Signal 1 is recognition of the tumor target by the T cell receptor (TCR), followed by signal 2, a co-stimulatory event (e.g., CD28) important for differentiating and expanding the T cell populations through secreted growth factors or ‘cytokines,’ notably interleukin-2 (IL-2). Note that the graphic illustrates TCR recognition of ‘MHCII-Ag,’ which is a cell surface complex specific for the CD4+ T cell subset. In the case of the CD8+ T cell subset, the TCR interacts with the ‘MHCI-Ag’ complex (not shown). Signal 2 on the T cell surface (for both subsets) is induced by CD28 binding to its cognate partner known as ‘B7’. Signals 1 and 2 are coined as the ‘gas petal’ or ‘clutch’, respectively. Once the tumor target is eradicated, the overall T cell response shuts down through a process involving immune checkpoint receptor-ligand interactions (not depicted here). However, in cancer, this negative regulatory process coined the ‘brakes’ is sustained, leading to T cell inactivation or ‘exhaustion’. (Modified from Sharma et al. Cancer Discov. 2021 Apr;11(4):838-857)
