Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13

Abstract

We have previously observed a novel role of natural killer T (NKT) cells in negative regulation of antitumor immune responses against an immunogenic regressor tumor expressing a transfected viral antigen. Here, we investigated whether hidden spontaneous antitumor immunosurveillance, in the absence of a vaccine, could be revealed by disruption of this negative regulatory pathway involving CD4؉ NKT cells and interleukin-13 (IL-13), in a murine pulmonary metastasis model of a nontransfected, nonregressor, syngeneic tumor, the CT26 colon carcinoma. The success of immunotherapy against cancer depends very much on how efficiently tumor antigens are presented to antigenspecific T cells and how effectively those T cells are activated to eradicate tumor cells. However, many tumor antigens targeted for immunotherapy by active immunization are self-antigens expressed not only in tumor cells but also in normal tissues. Thus, immune responses to tumor antigens are often limited by immunologic tolerance. 1,2 Most self-reactive T cells are deleted in the thymus and those leaking to the periphery are severely suppressed and fail to respond to antigens sufficiently to kill tumor cells. 3,4 Therefore, in order to increase the immunogenicity of tumor antigens and T cell responses against tumor cells, the suppressive mechanisms of peripheral tolerance must be overcome. Diverse approaches to accomplish this have been reported, such as expression of cytokines like granulocyte macrophage-colony stimulatory factor (GM-CSF), or costimulatory molecules, in tumor cells, 5-7 elimination of CD4 ϩ CD25 ϩ T regulatory cells 8 -11 and blockade of CTLA-4 12 or a combination of these. 13 A number of negative regulatory cells have been found to play a role in both autoimmune disease and cancer. 14 -16 One of the most widely studied T cells associated with immune suppression or tolerance is the immunoregulatory CD4 ϩ T cell constitutively expressing CD25 (the CD4 ϩ CD25 ϩ regulatory T cell). CD4 ϩ CD25 ϩ regulatory cells are considered to inhibit T cell activation irrespective of antigenic specificity. 14,17 Effective T cell immune responses against tumor were enhanced in mice by depletion of this T cell subpopulation in vivo. 8 -11 Another important but less widely studied regulatory cell is the natural killer T (NKT) cell. NKT cells comprise a novel T cell subset expressing NK cell markers, are CD4 ϩ CD8 -or CD4, CD8 double negative, and have a skewed ␣␤ T cell receptor (TCR) repertoire restricted by the nonclassic MHC class I-like CD1d molecule, which presents mostly glycolipid antigens rather than peptides. 18,19 While their detailed immunological functions remain unknown, NKT cells have been recently identified as one of the negative regulatory T cells, besides their roles as effector cells. 20 Regulatory CD4ϩ NKT cells produce large amounts of interleukin-4 (IL-4), which drives the differentiation and growth of T helper 2 (Th2) cells. 21,22 Thus, CD1d-restricted NKT cells could control physiological Th2-driven immune responses and indire...

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

“…In addition, a soluble form of IL-13R 2 can prevent IL-13-mediated suppression of tumor immunosurveillance. 26,27 Therefore, i.t. introduction of IL-13R 2 chain into established tumors may efficiently lead to activation of an antitumorigenic response and tumor immunosurveillance in tumor tissues.…”

“…14 IL-13 is a pleiotropic and Th2-dominated immune regulatory cytokine, 19,20 which plays a central role in allergic asthma [21][22][23] and mediates diverse responses during helminth infection. 24,25 It is critical for tumor immunosurveillance 26,27 and modulates apoptosis or tumor cell growth. 28,29 Two different components of the IL-13 receptor have been identified, which are known as IL-13R 1 chain [30][31][32] and IL-13R 2 chain.…”

“…[39][40][41] Moreover, IL-13R 2 chain may inhibit IL-13-mediated biologic functions in tumor growth and recurrence. 26,27,42,43 To utilize the attractive properties of IL-13R 2 chain in IL-13 cytotoxin-mediated cancer therapy, we previously tried to combine the cytotoxin treatment with gene transfer of IL-13R 2 chain. 13,14,[44][45][46] In the present study, we generated a replicationdefective adenovirus, Ad-IL-13R 2, which can express high levels of IL-13R 2 chain in infected cells.…”

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

“…Paradoxical role of NKT cells in tumor immunity. With this background in which the predominance of the literature suggested that type I invariant NKT cells were protective against tumors based on a Th1 bias, it was surprising to find that NKT cells could also suppress tumor immunosurveillance based on their production of the Th2 cytokine IL-13 (93)(94)(95)(96)(97), even though they contributed to asthma or protected against some autoimmune diseases based on a Th2 bias. Recurrence of a murine regressor tumor was found not to occur if CD4 ϩ regulatory cells were depleted, and these CD4 ϩ cells were found to be CD1d-restricted NKT cells (93), not CD4 ϩ CD25 ϩ Treg cells (98).…”

Type I natural killer T cells: naturally born for fighting

“…It is clear that NKT cells that are protective against tumors are skewed toward Th1 cytokines, while type ІІ NKT cells suppress tumor immunosurveillance based on their production of Th2 cytokines [53] . The potentially opposite effect of these two subsets of NKT cells was also determined in CD1d KO mice lacking both subtypes of NKT cells with decreased production of Th1 and Th2 cytokines but Jα18 KO mice lacking only NKT cells with reduced IFN-γ during murine schistosomiasis [54] .…”