Tumor-Binding Allogeneic IgG Stimulates Antitumor T-Cell Responses

Genetically and immunologically dissimilar allogeneic tumors, similar to transplanted organs, are consistently rejected by host T-cell immunity in animal models. An understanding of the mechanisms underlying allogeneic tumor rejection may inform new strategies in cancer immunotherapy, prompting Carmi and colleagues to explore the basis of tumor eradication in MHC-matched allogeneic mice. Allogeneic tumor rejection in mouse models of melanoma and metastatic pancreatic cancer was initiated by naturally occurring IgG antibodies, which bound tumor cells and stimulated tumor-antigen processing and presentation by dendritic cells (DC), resulting in subsequent proliferation of tumor-reactive T cells. Systemic administration of syngeneic DCs loaded with allogeneic IgG immune complexes protected against tumor relapse in mice. Although intratumoral injection of allogeneic IgG was not sufficient to inhibit tumor growth, combined administration with adjuvant DC stimuli, such as CD40 ligand and TNFα, facilitated activation of tumor-associated dendritic cells (TADC), induction of antitumor T-cell–mediated immune responses, and almost complete resolution of established syngeneic primary melanoma, lung, and breast tumors, as well as elimination of distant metastases. Mechanistically, allogeneic IgG–mediated tumor rejection was dependent on binding of IgG to the tumor-cell surface via membrane proteins that are expressed on some normal cells as well as tumor cells. However, the antigens recognized by tumor-reactive T cells were tumor-specific, possibly explaining why there was little or no damage to normal tissues in treated mice. Allogeneic IgG in combination with DC stimuli activated human TADCs isolated from patients with lung cancer, and DCs from patients with malignant pleural mesothelioma incubated with their own tumor cells bound with allogeneic IgG induced autologous T-cell proliferation. Overall, these findings demonstrate that allogeneic tumor-binding IgG combined with DC stimuli promote potent T-cell–mediated antitumor immunity and suggest that this mechanism may guide future development of cancer immunotherapies.

Carmi Y, Spitzer MH, Linde IL, Burt BM, Prestwood TR, Perlman N, et al. Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity. Nature 2015;521:99–104.