Tumor-binding antibodies and tumor immunity

The remarkable capacity of the immune system to distinguish self from non-self makes it almost impossible to transmit cancers (or organs) from one individual to another in the absence of immunosuppressive drugs. Whereas rejection of donor cells bearing mismatched MHC alleles has been ascribed to direct activation of T cells by the altered MHC-peptide structures, the factors that initiate rejection of MHC-matched donor cells remain elusive. Our recent study identified these factors [1]. We found that whereas tumor cells grow steadily in syngeneic hosts, they spontaneously regress following transfer to MHCI and II matched allogeneic hosts, in a T cell-dependent manner. In such hosts, tumor reactive T cells were found to proliferate in secondary lymphoid organs and infiltrate tumor sites only after 5-6 days. At that time, the tumors were already infiltrated with activated dendritic cells (DC) that had consumed tumor cells and were processing their antigens in a stimulatory context, as indicated by their expression of CD40 and CD86 and secretion of IL-12. By contrast, DC in syngeneic tumors did not have an activated phenotype or evidence of tumor uptake. Importantly, when DC from naïve animals were cultured with allogeneic or syngeneic tumor cells, they did not become activated or ingest tumor cells, indicating that other factors present in tumor-bearing hosts must play a role in these processes. Further investigation revealed that the improved DC activation observed in allogeneic hosts results from the actions of pre-existing naturally occurring IgG antibodies that bind tertiary protein structures on the surface of allogeneic tumor cells. Thus, the rapid (within hours) binding of injected tumor cells by these alloantibodies is a key element that enables tumor-infiltrating DC to process tumor antigens and present them in a stimulatory context to CD4 + T cells. The discovery that natural antibodies initiate the rejection of allogeneic tumors led us to assess the impact of these antibodies on tumors that arise in the autologous setting. The effects of tumor-binding IgG during autologous tumor initiation and progression have been a source of controversy for many years. On the one hand, circulating antibodies against p53 are associated with poor prognosis and metastases in a variety of human cancers (reviewed in [2]). Moreover, in µMT mice that lack B cells, vaccination with irradiated tumor cells promoted a protective Th1-biased immune response, while vaccination of wild-type animals generated a poorly protective Th2-biased response [3]. In other studies tumor-binding IgG was shown …