Lifting the innate immune barriers to antitumor immunity

Abstract

The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects-cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

Keywords: dendritic cells; immunity, innate; inflammation; lymphocyte activation; macrophages.

Figure 1

A constellation of innate immune cells sculpts the environment for effective T cell-mediated killing of cancer cells. While T cells are commonly the effectors of antitumor immunity, a panoply of innate immune cells including macrophages, dendritic cells, natural killer cells, endothelial cells and stromal cells such as cancer-associated fibroblasts and mesenchymal cells can regulate the efficiency of T cell activation and tumor infiltration.

Figure 2

Activating and inhibitory molecules in innate immune cells regulate their antitumor immune functions. Both activating and inhibitory molecules regulate innate immune cell function or are produced by innate immune cells in the context of the antitumor immune response. A few examples of activators and inhibitory molecules that regulate or are produced by innate immune cells are shown. Green upward arrow indicates molecules that enhance antitumor immunity, while red downward arrow indicates molecules that inhibit the antitumor immune response. Overexpression or induction of the function of activators can boost antitumor immunity; similarly, the blockade of the inhibitors that dampen antitumor immunity should also drive a more effective antitumor response. FAP, fibroblast activation protein; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IL, interleukin; RTKs, receptor tyrosine kinases; TLR, Toll-like receptor; TNFα, tumor necrosis factor α.