Abstract
The anti-CTL-associated antigen 4 (anti-CTLA-4) antibody ipilimumab is the first agent to show improved survival in a randomized phase III trial that enrolled patients with metastatic melanoma. Studies are ongoing to identify mechanisms that elicit clinical benefit in the setting of anti-CTLA-4 therapy. We previously reported that treated patients had an increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule, a T-cell-specific molecule that belongs to the CD28/CTLA-4/B7 immunoglobulin superfamily. ICOS and its ligand (ICOSL) have been shown to play diverse roles in T-cell responses such as mediating autoimmunity as well as enhancing the development/activity of regulatory T cells. These seemingly opposing roles have made it difficult to determine whether the ICOS/ICOSL pathway is necessary for antitumor responses. To determine whether the ICOS/ICOSL pathway might play a causal role in the antitumor effects mediated by anti-CTLA-4, we conducted studies in ICOS-sufficient and ICOS-deficient mice bearing B16/BL6 melanoma. We show that ICOS(+) T cells comprised a population of Th1 cytokine producing and tumor antigen-specific effector cells. Furthermore, in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 are significantly diminished, thereby impairing tumor rejection. Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti-CTLA-4 therapy.
Highlights
T-cell responses are initiated by T-cell receptor signaling, additional costimulatory and coinhibitory signals regulate the outcome of T-cell activation
We previously reported that treatment of cancer patients with anti–CTL-associated antigen 4 (CTLA-4) therapy led to an increase in the frequency of ICOSþ T cells in both tumor tissue and systemic circulation [15,16,17]
We analyzed the frequency of ICOSþ T cells in CD4 and CD8 populations from spleen, tumor draining lymph nodes (DLN), and tumor infiltrating lymphocytes (TIL) of untreated and treated wt mice
Summary
T-cell responses are initiated by T-cell receptor signaling, additional costimulatory and coinhibitory signals regulate the outcome of T-cell activation. In a retrospective analysis of a small cohort of patients with metastatic melanoma treated with anti–CTLA-4, we found that a sustained increase in ICOSþ T cells correlated with increased survival [17] These data suggested that ICOSþ T cells might play an important role in antitumor immune responses. It was reported that melanoma www.aacrjournals.org cells expressing ICOS ligand promote the activation and expansion of Treg cells [27] These data would suggest that ICOS might play a role in suppressing antitumor responses. Our finding that CTLA-4 blockade in cancer patients results in an increase in the frequency of ICOSþ T cells that seem to correlate with clinical benefit is more consistent with a role for the ICOS/ICOSL pathway in enhancing antitumor responses. Our data suggest that the ICOS/ICOSL pathway can be targeted to enhance the efficacy of CTLA-4 blockade in cancer patients
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