Cancer and innate immune system interactions: translational potentials for cancer immunotherapy

Abstract

Passive immunotherapy, including adoptive T-cell therapy and antibody therapy, has shown encouraging results in cancer treatment lately. However, active immunotherapy of solid cancers remains an elusive goal. It is now known that the human innate immune system recognizes pathogen-associated molecular patterns conserved among microbes or damage-associated molecular patterns released from tissue injuries to initiate adaptive immune responses during infection and tissue inflammation, respectively. In contrast, how the innate immune system recognizes endogenously arising cancer remains poorly understood at the molecular level, which poses a significant roadblock to the development of active cancer immunotherapy. We hereby review the current knowledge of how solid cancers directly and indirectly interact with cells of the human innate immune system, with a focus on the potential effect of such interactions to the resultant adaptive immune responses against cancer. We believe that understanding cancer and innate immune system interactions may allow us to better manipulate the adaptive immune system at the molecular level to develop effective active immunotherapy against cancer. Current and future perspectives in clinical development that exploits these molecular interactions are discussed.

Figure 1

Direct cancer recognition by the innate immune system. NK, macrophages, DC, neutrophils, eosinophils, and mast cells are the cellular components of the innate immune system. NKG2D, a stimulatory receptor on NK cells, specifically recognizes MICA/B on cancers to stimulate cell killing. Inhibitory receptors such as KIR detect non-classical MHC class I molecule HLA-G on cancers to prevent NK cell cytotoxicity. Binding of TNF family ligands on NK cells to TNF family receptors on tumor cells triggers cancer apoptosis, which gives rise to subsequent CD4⁺ and CD8⁺ T cells. The function of NK cells is also mediated by activating FcR/CD16 through ADCC. Macrophages phagocytose apoptotic cancer cells via CD14, TIM, TAM and FcR receptors through the interaction with ICAM-3, PS, PS/Gas6 and immune complex, respectively. Gas6 functions as the “bridge” between PS and TAM receptors. Both activating and inhibitory Fc receptors (FcR⁺, activating; FcR⁻, inhibitory) exist on macrophages and associate with the production of cytokines and superoxide substances. DC may uptake apoptotic tumor cells through α_vβ₅, CD36, FcR, TIM and TAM receptors. Cytokine secretion from DC and macrophages promote antigen presenting cell activation, leading to cellular and humoral adaptive immune response. Activating FcR on DC help tumor cell antigen presentation. Activating and inhibitory FcR are also expressed on neutrophils, eosinophils, and mast cells, which directly recognize antibody-coated tumors to promote or inhibit the secretion of cytokines and chemokines from innate immune cells.