The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy

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 þ 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. Cancer Res; 71(16); 5445-54. Ó2011 AACR.

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

“…10 This observation is in line with previous reports showing that this T cell subpopulation was upregulated both in the peripheral blood and at tumor site of MM patients following IPI treatment. 19,22,23,28,[30][31] The evidence that IPI treatment of MM patients can upregulate the frequency in the periphery of memory/activated T cell subsets was also observed in our study. [24][25][26][27][28] Taken together these observations corroborate the hypothesis that changes of the frequency of circulating T cell subsets from patients enrolled in the NIBIT-M1 study resulted from the activity of the checkpoint blockade agent and were not affected by chemotherapy.…”

“…12,[19][20][21] ICOS C T cells that were augmented by IPI therapy in tumor lesions from prostate cancer patients, represented lymphocytes endowed with antitumor activity. 22,23 Moreover, increased levels in the periphery of central memory or effector memory CD4 C and CD8 C T cells have been described in patients undergoing IPI treatment, although there was no correlation with the clinical outcome. [24][25][26][27][28] A novel multifaceted immunomonitoring has been set up in the context of the NIBIT-M1 study, with the aim to determine simultaneously phenotypic and functional changes in circulating T cells from MM patients treated with IPI plus FTM.…”

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV + tumors when combined with an E6/E7 peptide vaccine

“…Administration of peptide vaccine alone increased the frequency of ICOS + CD8 T cells greater than fourfold relative to untreated mice. In accordance with recent publications, αCTLA-4 therapy also increased the infiltration of tumors by ICOS + T cells, although not to a level that reached statistical significance (22,23). Addition of the peptide vaccine to αCTLA-4 promoted a threefold higher frequency of ICOS + CD8 T-cell infiltration (28% versus 9%) relative to antibody monotherapy.…”

“…Whereas CTLA-4 and PD-1 blockade are known to promote ICOS up-regulation, 4-1BB agonist does not (7). Given that ICOS expression has been associated with enhanced T-cell effector function and prolonged survival, we hypothesize that the ICOS + ThEO and TcEO T cells formed by the combination of vaccination and α4-1BB may have an unparalleled potential to eliminate established tumors (22,23). Our data suggest that either direct or indirect action of the αGalCer adjuvant at the vaccine site must contribute to ICOS induction as peptides alone or α4-1BB antibody alone have not been reported to have this effect.…”

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…3G), which is a positive biomarker of αCTLA-4 therapeutic and clinical responses. 24 Moreover, vistusertib/αCTLA-4 combination significantly enhanced the proportion of IFNγ expressing CD8 + T-cells (Fig. 3H).…”