TNFR1 Signaling and IFN-γ Signaling Determine whether T Cells Induce Tumor Dormancy or Promote Multistage Carcinogenesis

Abstract

No therapeutic cancer vaccine has yet shown sufficient efficacy to be approved in the U.S., in part because of the complex immune response to vaccination. A study in Cancer Cell helps refine the tactics for developing pancreatic cancer vaccines, showing that local activity by tumor-seeking helper T cells can retard-or promote-tumor development. 1 The study, conducted by a team led by Martin Röcken, professor of dermatology at Eberhard Karls University, could help cancer vaccine makers design therapies that direct T cells to the right place and elicit the right kind of immune response. The group used an established mouse model in which overexpression of a viral oncoprotein called T antigen (TAG) promotes islet cell adeno-mas and, eventually, carcinomas in the pancreas. 2 Such tumors develop extensive vascular structures that facilitate tumor growth. The researchers raised helper T cells that recognized a TAG fragment in cell culture. The T cells were labeled with a fluorescent dye and injected into mice. Within days, the TAG-seeking T cells migrated to pancreatic lymph nodes in TAG-expressing mice but not in wild-type controls. Once on the scene, the T cells prevented both the appearance of new tumors and the expansion of existing ones beyond the adenoma stage. Compared with mock-treated controls, mice that received TAG-specific T cell transfusions had fewer and smaller pancreatic tumors with less extensive vascularization. T cell-treated mice, including those treated after tumors started to form, lived longer than mock-treated controls. "We show that T cells can induce tumor dormancy, " Röcken told SciBX. Playing TAG with tumors According to conventional wisdom, helper T cells act indirectly in cancer vaccines by secreting cytokines that prompt cytotoxic T cells to attack tumors. This principle is the basis of several therapeutic cancer vaccines. 3 However, Röcken's team found that mice lacking most of their cytotoxic T cells still could benefit from TAG-specific helper T cells. Although the pancreatic tumors of these T cell-treated mice showed no signs of apoptosis, which would be indicative of cytotoxic T cell attack, the researchers did see a decrease in the pancreatic incorporation of bro-modeoxyuridine (BrdU) compared with that seen in wild-type controls. BrdU labels newly replicated DNA in proliferating tumors.

Targeting Stat3 Induces Senescence in Tumor Cells and Elicits Prophylactic and Therapeutic Immune Responses against Breast Cancer Growth Mediated by NK Cells and CD4+ T Cells

“…In line with this evidence, in this work, we demonstrated that DCs from mice immunized with Stat3Y705F-C4HD cells cocultivated with C4HD cells were able to upregulate CD86 and MHC class II molecules, markers of DC maturation. Importantly, tumor cells transfected with DN Stat3 vector or treated with JSI-124 released TNF-a and IFN-g, which can act synergistically to induce signaling in Ag-specific CD4 + T cells that prevents tumor angiogenesis, tumor cell proliferation, and multistage carcinogenesis (29). In addition, these cells produced RANTES, which is involved in T cell migration and NK cell recruitment to tumors (30), and IP-10, which is a chemoattractant for resting NK cells and activated T cells (31).…”

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

“…It is clear from mouse models that adoptively transferred antigen-specific T cells are capable of eradicating established cancer (6)(7)(8), and the ability of CTLs to directly kill tumor and/or stromal cells is thought to be important for tumor elimination (9)(10)(11). Nonetheless, cytokines such as IFNg and TNFa produced by T cells are also likely to contribute to the prevention of tumor growth by ACT via mechanisms other than cell lysis (12)(13)(14).…”

Cancer-Immune Equilibrium: Questions Unanswered

“…In a study by Hermelink et al the adaptive tumor antigen specific T cells were found to arrest the growth of experimentally induced pancreatic tumors in mice in the presence of a coordinated interaction between IFN-γ and TNF. In the absence of this interaction [20]. In other studies also the IFNs have been suggested to provide a selective pressure that may lead to progression from elimination to equilibrium phase of the cancer immunoediting process [21].…”