Th17 cells in ovarian cancer

In this issue of Blood, Kryczek and colleagues show that a potent proinflammatory T-cell subset, IL-17–producing Th17 cells, can be found in ovarian cancers, and that their presence correlates with significantly enhanced survival.

Tumors express a variety of antigens, arising from mutations or aberrant processing, which ought to render them detectably “foreign” to the host immune system. Unfortunately, in most cases the patient's immune system fails to mount a protective response against these tumor-associated antigens. Yet some patients do appear to respond immunologically to their own tumors. When this happens, it is often a favorable prognostic sign.^1,2  What are the features of such a beneficial spontaneous antitumor immune response?

It is intuitively logical that a robust CD8⁺ cytotoxic T cell (CTL) response might predict a favorable outcome since CTLs directly kill tumor cells. Indeed, CD8⁺ infiltration into tumors has been shown to be associated with favorable prognosis.²  CD4⁺ T-cell responses may also be critically important in cancer, both in helping to recruit CD8⁺ CTLs to the tumor and in generating a local inflammatory milieu that supports the function of these CTLs within the tumor. However, the CD4⁺ arm of the immune system has not been as well characterized in antitumor responses. The situation is made more complex by the variety of CD4⁺ helper responses—Th1, Th2, and the recently described T-helper 17 (Th17) response—as well as the highly undesirable immunosuppressive regulatory T cell (Treg) response.

In the current study, Kryczek et al analyzed the tumor-infiltrating CD4⁺ T-cell population from 201 ovarian cancer samples for the presence of Th17 cells.³  Th17 cells play a potent proinflammatory role in certain infections and autoimmune disorders,⁴  and Th17 cells can display antitumor activity in certain mouse tumor models.⁵  However, the role of Th17 cells in human tumors has not been well studied. The authors found that some ovarian cancers contained a substantial fraction of tumor-infiltrating CD4⁺ T cells expressing interleukin-17 (IL-17), indicative of Th17 differentiation. Those patients with a higher number of tumor-infiltrating Th17 cells had significantly better overall survival, irrespective of their tumor stage (panel A in the figure). The presence of Th17 cells was found to be associated with multiple proinflammatory cytokines and chemokines. Th17 cells were also found to be inversely correlated with the number of tumor-infiltrating Foxp3⁺ Tregs, which have been previously shown to be an adverse prognostic factor in ovarian cancer.⁶  It is known that inducible Tregs and Th17 cells share a reciprocal differentiation pathway from uncommitted CD4⁺ precursors.⁴  In the current study, the authors show that macrophages isolated from ovarian tumors biased the in vitro differentiation of uncommitted CD4⁺ T cells toward Th17 cells. Therefore, the observed inverse correlation between Th17 cells and Tregs in tumors may reflect differing conditions within different tumors, favoring either inflammation (Th17) or suppression (Tregs). Furthermore, the Th17 and Treg lineages have recently been shown to be rather more plastic than previously thought, with several studies suggesting the possibility of interconversion between the 2 lineages.⁷  Thus, the inverse relationship between Th17 cells and Tregs observed in ovarian cancers may be more than simply a descriptive association. It may reflect fundamental differences in the nature of the spontaneous antitumor immune response—differences that appear to have significant impact on patient survival.

Finally, the Th17 cells in ovarian cancers were found to simultaneously express high levels of multiple other proinflammatory effector cytokines (IL-2, TNF-α, IFN-γ) in addition to IL-17 (panel B in the figure). In other settings, this so-called polyfunctional pattern of effector cytokine production has been associated with robust CD4⁺ response to infection and vaccination.⁸  Other investigators, including myself, have reported similar polyfunctional cytokine response by Th17-like cells in mouse tumor models as well.⁹  Thus, taken together, Kryczek et al have described a functionally important and hitherto unrecognized population of CD4⁺ T cells in ovarian cancers that favor enhanced inflammatory responses and reduced Treg-mediated suppression. The presence of these polyfunctional Th17 cells was statistically associated with better clinical outcome. This raises the question of whether a similar population could be therapeutically induced or expanded (eg, by vaccines or other active immunotherapy), and if this would likewise result in improved patient outcome.