Induction of tumoricidal function in CD4 T cells is associated with concomitant memory and terminally differentiated phenotype

Swim Across America Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065.
Journal of Experimental Medicine (Impact Factor: 13.91). 09/2012; 209(11):2113-26. DOI: 10.1084/jem.20120532
Source: PubMed

ABSTRACT Harnessing the adaptive immune response to treat malignancy is now a clinical reality. Several strategies are used to treat melanoma; however, very few result in a complete response. CD4(+) T cells are important and potent mediators of anti-tumor immunity and adoptive transfer of specific CD4(+) T cells can promote tumor regression in mice and patients. OX40, a costimulatory molecule expressed primarily on activated CD4(+) T cells, promotes and enhances anti-tumor immunity with limited success on large tumors in mice. We show that OX40 engagement, in the context of chemotherapy-induced lymphopenia, induces a novel CD4(+) T cell population characterized by the expression of the master regulator eomesodermin that leads to both terminal differentiation and central memory phenotype, with concomitant secretion of Th1 and Th2 cytokines. This subpopulation of CD4(+) T cells eradicates very advanced melanomas in mice, and an analogous population of human tumor-specific CD4(+) T cells can kill melanoma in an in vitro system. The potency of the therapy extends to support a bystander killing effect of antigen loss variants. Our results show that these uniquely programmed effector CD4(+) T cells have a distinctive phenotype with increased tumoricidal capability and support the use of immune modulation in reprogramming the phenotype of CD4(+) T cells.

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Available from: Jianda D Yuan, Jul 28, 2015
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    • "Definitely, the role for CD4+ T cells as effectors in antitumor immunity should be further intensively investigated, because—due to the complex biology of these cells—many issues still remain unexplained. The identification and characterization of their subclass acting as cytotoxic effectors, if it really exists as suggested [5] [29] "
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    ABSTRACT: In the recent past, it has repeatedly been reported that CD4 cells play an important role in the immunology of chronic myeloid leukaemia. It was therefore of interest to test their activity in an animal model using bcr-abl-transformed cells. BALB/c mice were four times immunized with a DNA vaccine carrying the bcr-abl fusion gene. Two weeks after the last vaccine dose, the animals were challenged with syngeneic bcr-abl-transformed 12B1 cells which form solid tumors after subcutaneous administration. At the time of challenge, animals were treated with antibodies against the CD8+ T cells or CD4+ T cells. The efficacy of the depletion was monitored and found highly effective. All nonimmunized animals developed tumors. All animals untreated with the antibodies as well as those in which CD8+ T cells had been depleted, were fully protected against the challenge. On the other hand, almost all mice treated with anti-CD4+ antibody developed tumors. These results strongly suggested that the CD4+ T cells acted as effectors in the present system.
    Clinical and Developmental Immunology 11/2013; 2013:923107. DOI:10.1155/2013/923107 · 2.93 Impact Factor
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    • "Our data also raise the question of whether antibodies targeting other co-inhibitory or co-stimulatory receptors also potentiate antitumor immune activity through intratumoral T reg cell depletion. Both -OX40 and -GITR mAb have been shown to induce a loss of T reg cells from the tumor microenvironment (Coe et al., 2010; Hirschhorn-Cymerman et al., 2012), although the mechanisms remained obscure. Furthermore , the apparent duality of function of such antibodies, e.g., -OX40 targeting both the T eff and T reg cell compartments (Piconese et al., 2008), has been previously noted. "
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    ABSTRACT: Treatment with monoclonal antibody specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti-CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fcγ receptor-expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context-dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4-based cancer immunotherapy, and illustrate the importance of specific features of the local tumor environment on the final outcome of antibody-based immunomodulatory therapies.
    Journal of Experimental Medicine 07/2013; 210(9). DOI:10.1084/jem.20130579 · 13.91 Impact Factor
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    • "We have termed this CD4 T cell phenotype ThEO and the corresponding CD8 T cell phenotype TcEO. A recently published manuscript provides strong support for our observations, as they show that Trp1 melanoma-specific CD4 T cells can be rendered capable of eradicating large established tumors when adoptively transferred into mice treated with cyclophosphamide and OX-40 (Hirschhorn-Cymerman et al., 2012). They show that the enhanced cytotoxicity of these cells is dependent on Eomes and that they up-regulate KLRG1, demonstrating that they have taken on the ThEO polarity described here. "
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    ABSTRACT: 4-1BB agonist antibody treatment induces a population of KLRG1(+) T cells that infiltrate melanoma tumors. We investigated the origin and function of these cells, as well as their place within established T cell paradigms. We find that these T cells, particularly the CD4 lineage, represent a novel phenotype characterized by enhanced, multipotent cytotoxicity. Distinct from described polarities, this T cell phenotype is driven by the T-box transcription factor Eomesodermin. Formation of this phenotype requires 4-1BB signaling on both T and antigen-presenting cells and the resulting production of the cytokines IL-27, IL-15, and IL-10. Furthermore, we find CD4(+) T cells bearing the signature features of this phenotype in the livers of mice infected with both bacterial and viral intracellular pathogens, suggesting a role for these cells in infectious immunity. These T cells constitute a novel phenotype that resolves multiple questions associated with 4-1BB activation, including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity.
    Journal of Experimental Medicine 04/2013; 210(4). DOI:10.1084/jem.20121190 · 13.91 Impact Factor
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