The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy
Open Access
- 11 August 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 71 (16), 5445-5454
- https://doi.org/10.1158/0008-5472.can-11-1138
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. Cancer Res; 71(16); 5445–54. ©2011 AACR.Other Versions
This publication has 47 references indexed in Scilit:
- Melanoma Cells Express ICOS Ligand to Promote the Activation and Expansion of T-Regulatory CellsCancer Research, 2010
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical TrialClinical Cancer Research, 2010
- Anti-CTLA-4 therapy results in higher CD4 + ICOS hi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissuesProceedings of the National Academy of Sciences of the United States of America, 2009
- CTLA-4 blockade increases IFNγ-producing CD4 + ICOS hi cells to shift the ratio of effector to regulatory T cells in cancer patientsProceedings of the National Academy of Sciences of the United States of America, 2008
- Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanomaThe Journal of Experimental Medicine, 2008
- Two Functional Subsets of FOXP3+ Regulatory T Cells in Human Thymus and PeripheryImmunity, 2008
- SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockadeProceedings of the National Academy of Sciences of the United States of America, 2008
- Plasmacytoid dendritic cells prime IL-10–producing T regulatory cells by inducible costimulator ligandThe Journal of Experimental Medicine, 2007
- Checkpoint Blockade in Cancer ImmunotherapyAdvances in Immunology, 2006