Th9 cells promote antitumor immune responses in vivo

Abstract

Th9 cells are a subset of CD4 + Th cells that produce the pleiotropic cytokine IL-9. IL-9/Th9 can function as both positive and negative regulators of immune response, but the role of IL-9/Th9 in tumor immunity is unknown. We examined the role of IL-9/Th9 in a model of pulmonary melanoma in mice. Lack of IL-9 enhanced tumor growth, while tumor-specific Th9 cell treatment promoted stronger antitumor responses in both prophylactic and therapeutic models. Th9 cells also elicited strong host antitumor CD8 + CTL responses by promoting Ccl20/Ccr6-dependent recruitment of DCs to the tumor tissues. Subsequent tumor antigen delivery to the draining LN resulted in CD8 + T cell priming. In agreement with this model, Ccr6 deficiency abrogated the Th9 cell-mediated antitumor response. Our data suggest a distinct role for tumor-specific Th9 cells in provoking CD8 + CTL-mediated antitumor immunity and indicate that Th9 cell-based cancer immunotherapy may be a promising therapeutic approach.

Tumor-specific IL-9–producing CD8+Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers

“…S7). Taken all together, these results thus far suggested that Tc9 cells may kill tumor cells independent of their secreted IFN-γ, possibly by using the cytolytic enzymes, and IL-9 provided critical help to their migration into tumor sites to exert effector function, which is an effect of IL-9 that has been extensively elucidated in our previous studies (15,17). Discussion CD8 + CTLs are thought to play a crucial role in tumor rejection, and extensive focus has been devoted to the study of CD8 + T cells in adoptive transfer protocols.…”

“…Interestingly, when mice were treated with IL-9-neutralizing antibodies, Tc9 cells largely failed to migrate into tumor tissues to exert long-lasting antitumor therapeutic effect. Given the important role of IL-9 in provoking inflammation in tumor sites and recruitment of lymphocytes (15,17), our results suggested that IL-9 secreted by Tc9 cells played an indispensible role for the homing of these cytolytic Tc1-like cells to tumor tissues and killing of tumor cells. These findings thus indicated that IL-9 rather than IFN-γ might be the critical cytokine contributed to the tumor destruction mediated by Tc9 cells.…”

“…IL-9 is a pleiotropic cytokine that has direct and indirect effects on multiple cell types (14). More recently, we and others reported that Th9 cell-derived IL-9 not only inhibited tumor progression, but also promoted greater tumor clearance than Th1 cells that have traditionally been considered as the most efficient CD4 + T-cell subset to generate antitumor immunity (15)(16)(17). It would be interesting to test under Th9-polarizing conditions whether naïve CD8 + T cells could also differentiate into IL-9-producing Tc9 cells, a potential CD8 + T-cell subset for ACT.…”

Human Vδ2 T cells are a major source of interleukin-9

“…Intriguingly, Th9 cells also appear to regulate tumor immunity. Although IL-9 and Th9 cells exerted antitumor activity in some solid tumor models (7,8), IL-9 actually promoted lymphoma development in other models (9). IL-9 is thus an important cytokine with multiple functions in the regulation of immune responses.…”

IL‐9 promotes the survival and function of human melanoma‐infiltrating CD4+CD8+ double‐positive T cells

“…Purwar et al reported that administration of rIL-9 or Th9 cells to tumor-bearing mice inhibited melanoma growth, through a mechanism dependent of mast cells [43]. In turn, Lu et al described another antitumor effect of IL-9 on melanoma lung metastasis, which through the induction of local CCL20 expression in the tumor microenvironment, led to an enhanced recruitment of dendritic cells and cytotoxic CD8 + T cells at the tumor site [58]. The ability of IL-9 to induce the secretion of chemotactic factors was also largely described in airway inflammatory pathologies [59].…”