Targeting FcαRI on Polymorphonuclear Cells Induces Tumor Cell Killing through Autophagy

Abstract

Neutrophils are the most abundant circulating FcR-expressing WBCs with potent cytotoxic ability. Currently, they are recognized as promising effector cells for Ab-mediated immunotherapy of cancer, because their capacity to kill tumor cells is greatly enhanced by tumor Ag-specific mAbs. The FcαRI represents the most potent FcR on neutrophils for induction of Ab-mediated tumor cell killing. However, the mechanisms of cell death that are induced are poorly understood. Because these mechanisms can be used for modulation of anticancer treatment, we investigated the tumor cell death induced by neutrophil-mediated Ab-dependent killing via FcαRI. Human mammary carcinoma cells were efficiently killed when incubated with human neutrophils and tumor-specific FcαRI bispecific or IgA Abs. Interestingly, we observed characteristics of autophagy such as autophagic structures by electron microscopy and LC3B+ autophagosomes in different human epithelial carcinoma cells, which resulted in tumor cell death. To a lesser extent, necrotic features, such as cellular membrane breakdown and spillage of intracellular content, were found. By contrast, apoptotic features including fragmented nuclei, Annexin V-positivity, and presence of cleaved caspase-3 were not observed. These findings indicate that neutrophils mainly facilitate autophagy to induce tumor cell death rather than the more commonly recognized apoptotic cell death mechanisms induced by NK cells or cytotoxic T cells. This knowledge not only reveals the type of tumor cell death induced in neutrophil-mediated, Ab-dependent cellular cytotoxicity, but importantly opens up additional perspectives for modulation of anticancer therapy in, for example, apoptosis-resistant tumor cells.

Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing

“…NK cells induce apoptosis in tumor cells through the release of granzymes and perforin. Cytotoxicity mediated by PMNs is less well understood, but it was reported that PMNs can mediate frustrated phagocytosis or induce autophagy in tumor cells by IgA (26).…”

The human immunoglobulin A Fc receptor FcαRI: a multifaceted regulator of mucosal immunity

“…128 It is therefore likely that the amplitude of signals mediated through Fc RI or Fc R also differs, as interaction of Fc RI with FcR -chain is stronger because of an electrostatic interaction ( Figure 2 ) that is absent for Fc R. 102 An attractive feature of recruiting neutrophils as effector cells is the fact that targeting Fc RI on neutrophils was recently demonstrated to induce autophagic tumor cell death (and necrosis to a lesser extend). 188 As such, neutrophils may be able to kill tumor cells with mutations in apoptotic pathways. Moreover, neutrophils attract Th17 cells, which have been shown to have a role in anti-tumor immunity, 189,190 and moreover secrete cytokines and chemokines that attract other immune cells (monocytes or DCs), which may result in more generalized anti-tumor immune responses.…”

Immunoglobulin A: magic bullet or Trojan horse?

“…Neutrophils were shown to induce several antitumour effector functions in vitro, including antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), recruitment of other immune cells, the release of cytotoxic molecules, and the induction of necrosis and autophagy [42][43][44][45]. Additionally, neutrophils release NETs, which were shown to hamper tumour cell growth by inducing apoptosis and/or inhibiting proliferation [46].…”