Tumor-specific Th17-polarized cells eradicate large established melanoma

Abstract

IntroductionThe role of CD4 ϩ cells in antitumor immunity remains controversial and poorly understood. 1,2 They are known to mediate potent therapeutic effect in the setting of hematopoietic stem cell allotransplantation and donor lymphocyte infusion in hematologic malignancy, 3,4 but antigen-specific T helper (Th) cells have been studied to much lesser extent. A lack of clarity regarding CD4 ϩ cells is due, in no small part, to the complexity of their biology. CD4 ϩ T cells can differentiate into diverse subsets with specific phenotypes that can have self-reinforcing and opposing functions, but these T-cell subsets have not been comprehensively studied in tumor-bearing mice.Historically, CD4 ϩ T lymphocytes have been thought of as mere providers of stimuli to help the putatively more important CD8 ϩ effectors, which eliminate cancer by direct cytotoxicity. [5][6][7] There are several studies showing that CD4 ϩ T helper (Th) cells are capable of protecting the host against tumor challenge and even of mediating tumor regression on their own in the setting of either solid or hematopoietic disease. [8][9][10][11][12][13] Furthermore, protection was maintained against MHC class II-negative multiple myeloma model and involved cross-presentation by professional antigenpresenting cells (APCs) and activation of tumoricidal activity mediated by macrophages secreting IFN-␥. 14 A similar IFN-␥-dependent mechanism was involved in the rejection of MHC class II-negative tumor in severe combined immunodeficient (SCID) mice. 15 In some cases, the ability to reject antigen-expressing tumor by specific naive Th cells was thought to be substantially better than the ability of CD8 ϩ cells. 16 Classically, effector CD4 ϩ T cells have been categorized into T helper 1 (Th1) and T helper 2 (Th2) subsets. 17,18 Limited studies indicate that both subtypes elicit antitumor effects, 19-21 but the Th1-polarized cells, secreting IFN-␥ and capable of enhancing activity of cytotoxic CD8 ϩ lymphocytes, have traditionally been regarded as more efficient. [22][23][24][25] However, it is also clear that CD4 ϩ T regulatory cells (T regs ) can efficiently suppress the function of antitumor CD8 ϩ T cells. 5,[26][27][28] Recently, the novel Th17 lineage, generated in the presence of TGF-␤ and IL-6 and expanded under the influence of IL-23, [29][30][31] has been associated with responses against certain infections and implicated in the development of autoimmunity in animal models that had been previously linked to Th1-type responses (experimental autoimmune encephalitis, collagen-induced arthritis). 32,33 They also seem to play an important role in the pathogenesis of graft-versus-host disease (GVHD). 34,35 Th17 cells have been found in various tumors, including mycosis fungoides, Sézary syndrome, and prostate cancer. 36,37 Kryczek et al reported the presence of naturally occurring Th17 cells and T regs in the tumor microenvironment and tumor-draining lymph nodes in both human and mice tumors. 38 Proinflammatory cytokines including IL-17A, IL-6, and I...

Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response

“…In fact, our data are consistent with recent findings showing that Th17 cells producing IFN-g are capable of mediating regression of established tumors in some murine models. 44,46,47 Collectively, our data suggest that, in our model, Th17-polarized cells mainly mediated tumor 45 Further studies with a selective depletion of effector cells will help to elucidate the exact role that these cells have in the observed antitumoral effect. In summary, we have shown that hybrids of tumor cells and DCs transduced with CD40L induce systemic antitumor immunity, which, in contrast to untransduced fused cells, can eradicate established tumors.…”

“…42,43 The fact that both IL-2 and IFN-g secretions have been detected mainly in cells from FC-CD40L-vaccinated mice suggests that Th1 cells could be involved in an antitumoral effect. However, as both human and murine Th17 cells produce IL-2 and IFN-g (that is, the so-called Th17-1), 44,45 we cannot rule out Th17 cells as the main source of this cytokine. In fact, our data are consistent with recent findings showing that Th17 cells producing IFN-g are capable of mediating regression of established tumors in some murine models.…”

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

“…To our knowledge, this is the first report demonstrating tumor-promoting properties of gd T cells, which is quite different from the generally reported tumor-inhibiting properties of skin-resident Vg5 1 gd T cells. Recent studies have shown that tumor antigen-specific Th17 or Tc17 cells, which were induced in vitro, were converted into IFN-g-producing cells after transfer into tumor-bearing mice and subsequently eradicated tumor cells [45,46]. In contrast, IL-17-producing gd T cells did not produce IFN-g in the tumor microenvironment in parallel with the decrease of their cytotoxic function.…”

“…Therefore, we now investigated whether Th1 cell therapy or introduction of Th1 immunity by IL-12 can induce a plasticity in IL-17-producing gd T cells, namely, alter pro-to anti-tumor IL-17-producing gd T cells. Recently, it has been reported that IL-17-producing cells exhibited anti-tumor immunity in vivo in an IFN-g-dependent manner [46]. Therefore it might be possible to control pro-tumor and anti-tumor properties of IL-17-producing gd T cells by introducing Th1-dominant immunity at tumor-local site.…”

CD4+ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

“…Little is known, however, about the risk of autoimmune pathology caused by CD4 1 effector T cells and the mechanisms regulating their functions against cancerous and normal tissues. Some insight can be gained from a recent publication that found the anti-tumor potency of CD4 1 T cells was directly related to their capacity to produce depigmentation in the skin [13], reinforcing the concept that these two processes are linked.…”