Spotlight

Abstract

Geng et al., pp. 2657–2664 Harnessing the immune system with tumor-specific antigens is a powerful approach in cancer therapy. Although tumor vaccines are successful in inducing high frequencies of tumor-specific T cells, this induction does not always coincide with tumor regression. A model has evolved such that residual tumor cells develop active mechanisms to alter the activity of invading T cells within the tumor microenvironment. Geng and colleagues have uncovered one powerful mechanism of tumor immune resistance. They observed that in mice bearing B16F1 melanomas, vaccination with melanoma peptide and recombinant HSP70 chaperone resulted in a dramatic reduction in the number of lung metastases. This reduction coincided with a large number of tumor-invading T cells, which produced plenty of Th1 cytokines such as IL-2 and interferon-g. However, after an extended period of time (day 28), the tumor relapsed and the treated mice developed metastatic foci similar to those in untreated mice. When the authors examined residual tumor cells, they found that expression of the B7-H1 cell surface molecule was enhanced in mice that had received the combination vaccine, but not in mice treated with saline or the melanoma peptide alone. B7-H1 (also known as PD-L1) is widely expressed on cells of the lymphoid system and nonlymphoid tissues and also found in many tumors, and has profound effects on the regulation of T cells. Its interaction with the PD-1 receptor expressed on activated T cells is implicated in the regulation of tumor immune resistance. Since vaccinated animals showed a higher induction of B7-H1 expression than control animals, the authors speculated that the Th1 cytokine response after vaccination induced the expression of the immune suppressor. Indeed, treatment of B16F1 cells with increasing amounts of interferon-γ induced strong upregulation of B7-H1 surface expression. Combination treatment of mice with HSP70 vaccine and a plasmid expressing the soluble PD-1 receptor to block B7-H1 activity enhanced the Th1 response of tumor-infiltrating T cells and resulted in a significantly prolonged survival. More than 80% of mice treated with the combination treatment survived at day 80. Future vaccination studies must take into account that the immune response induced by tumor vaccine might lead to the unwanted induction of immune suppressors such as B7-H1. The neutralization of the B7-H1/PD-1 interaction is an important addition to antitumor immunotherapeutic strategies. Kwak et al., pp. 2711–2720 Angiogenesis is an essential participant in wound healing, embryonic development, chronic inflammation, cancer and metastasis and is tightly regulated by a balance between inhibitors and stimulators, including the key factor, vascular endothelial growth factor (VEGF-A). In particular, VEGF-A is the most important angiogenic factor in neovascularization in human tumors. It is also an important tumor marker and induces angiogenesis by binding to two receptor tyrosine kinases, KDR/Flk-1 and Flt-1. In this issue of the IJC, Kwak and colleagues report that emodin, a tyrosine kinase inhibitor extracted from Chinese herbs, can inhibit angiogenesis by blocking the phosphorylation of the KDR/Flk-1 receptor. Emodin blocked many VEGF-dependent assays associated with angiogenesis, including proliferation, migration and tube formation of umbilical vein endothelial cells (HUVECs). In vivo, emodin also blocked neovessel formation in several experimental systems. These observations highlight the possible efficacy of emodin in controlling neovessel formation in diseases associated with neoangiogenesis. McNally et al., pp. 2840–2846 When suddenly an unusually high incidence of the same disease is observed in a small geographical location, it is highly likely that an infectious agent is at work. Epidemiologists use such space-time clustering to uncover infectious components of a disease. However, it is predicted that only rare infections and infections with a relatively constant lag time between infection and diagnosis would cause space-time clustering. McNally and colleagues conducted the largest study of space-time clustering to date to examine childhood cancers in Great Britain (32,295 cases). They report statistically significant space-time clustering for all leukemias, especially acute lymphoblastic leukemia (ALL) for the ages 1–4 years (p = 0.03). Significant space-time clustering was also observed for soft tissue sarcoma and osteosarcoma, but not for all bone tumors. In contrast to previous studies, no significant result was obtained for CNS and Wilms tumors. In addition, lymphomas, including Hodgkin lymphoma, did not show significant space-time clustering. At first sight, this result indicates that infectious agents are not involved in the etiology of lymphomas. However, it could also indicate that a ubiquitous infectious agent might contribute to lymphomagenesis. Yet another possibility is that infections occurred in utero. The authors point out that their analysis was based on dates and places of diagnosis. Dates and places of birth were not available.