IL11: A Specific Repressor of Tumor-Specific CD4⁺ T Cells

There are myriad tumor-intrinsic and -extrinsic mechanisms that dampen T-cell–mediated antitumor immunity. When naïve CD4⁺ T cells recognize their cognate antigen in the context of MHC, a process of massive proliferation and differentiation to cells with distinct cytokine profiles is started. Rather than being irreversibly committed, CD4⁺ T cells retain plasticity with respect to the cytokines they can produce, which allows them to adjust their activity as cues in the local environment change (1). Tumors can exploit this plasticity to escape the immune system by producing cytokines that (in)directly influence T-cell activity, such as IL10, TGFβ, and IL6 (2).

IL11 is a member of the IL6 family of cytokines. Like IL6, IL11 is a pleiotropic cytokine, with a major role in hematopoiesis and oncogenesis. Although IL6 is produced by many types of cells, IL11 is predominantly produced by stromal cells, in particular following stimulation with TGFβ. Overexpression of each of these cytokines is seen in several cancers and is associated with poor prognosis and suppression of inflammation (3). Although there are sporadic clues in the literature suggesting that IL11 may repress T helper 1 (Th1) polarization, it has been unclear if and how IL11 affects antitumor immunity. Huynh and colleagues are the first to provide robust evidence for a tumor cell–extrinsic role for IL11 in suppressing antitumor immunity (4).

Using two colorectal cancer models in wild-type and IL11ra^−/− mice, Huynh and colleagues show that tumor growth is reduced in mice lacking the IL11RA. They observe no gross alterations in immune infiltrate composition when IL11 signaling is abrogated, but CD8⁺ T cells displayed an increased expression of perforin, whereas IFNγ and TNFα were increased in CD4⁺ T cells. In addition, production of Th1 cytokines by CD4⁺ but not CD8⁺ T cells is suppressed by in vitro treatment with IL11. To separate the role of IL11 signaling in T cells from signaling in other cells, the authors use an elegant combination of adoptive bone marrow transfers, showing that lack of IL11 signaling in the hematopoietic compartment is associated with reduced tumor burden. Through antibody-mediated CD4⁺ or CD8⁺ T-cell depletion in IL11ra^−/− mice, they reveal a complete dependency of tumor control on CD4⁺ T cells. How this control is mediated is still unclear and requires further studies focusing on the role of the Th1 cytokines and innate cells, which also express IL11RA but are recruited and activated by IFNγ. In the models that Huynh and colleagues use, tumor immunity is suppressed by regulatory T cells (Treg), which express high levels of IL11RA, but the authors show that CD4⁺ T-cell depletion impairs the antitumor effect in IL11ra^−/− mice, indicating that the antitumor effect is not due to loss of IL11 signaling in Tregs. The fact that IL11 has no effect on Th1 production by CD8⁺ T cells with a functional IL11RA poses the question as to whether this is related to a different mix of transcription factors and repressors in CD8⁺ T cells (1). Understanding the impact of IL11 on the size and function of the recently identified important cluster of CD39⁺CD4⁺ tumor-specific T cells (5) may also offer a better insight into the impact of IL11 overexpression in cancer.

S.H. van der Burg reports personal fees from ISA Pharmaceuticals, AGLAIA, PCI Biotech, and DCprime outside the submitted work.