Comparable in vivo efficacy of CD28/B7, ICOS/GL50, and ICOS/GL50B costimulatory pathways in murine tumor models: IFNγ-dependent enhancement of CTL priming, effector functions, and tumor specific memory CTL

Zuberek, Krystyna; Ling, Vincent; Wu, Paul W.; Ma, Huiyuan; Leonard, John P.; Collins, Mary; Dunussi‐Joannopoulos, Kyriaki

doi:10.1016/j.cellimm.2003.09.002

Cited by 20 publications

(16 citation statements)

References 37 publications

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“…Because ICOS is expressed on all T cells after activation, it is actually not surprising that T reg cells also express ICOS, as previously published (42,43 (44,45) or ICOSL-expressing tumor cells (46,47). It is important to note that the ICOS/ICOSL pathway is tightly regulated by feedback loops (48), and careful consideration will need to be given to the approaches that are undertaken to target this pathway for cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 96%

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

2011

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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.

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Section: Discussionmentioning

confidence: 96%

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

2011

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“…on June 19, 2019. by guest www.bloodjournal.org From cell lymphoma cells. 159 Although induced ICOS-L expression enhances cytotoxic T cell-mediated tumor rejection, [160][161][162] there is sparse and conflicting evidence for its expression in solid tumors, 163,164 while expression in myeloma 165,166 and acute leukemia is widely heterogeneous. 71, 166 Despite these sometimes contradictory findings, the ICOS/ICOS-L axis may yet have an indirect role in enhancement of tumor immunity.…”

Section: Icos and B7-h2 In Cancermentioning

confidence: 99%

The role of B7 family molecules in hematologic malignancy

Greaves

Gribben

2013

Blood

156

125

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IntroductionCancer and the immune system are fundamentally interrelated. 1,2 Cancer cells express tumor-specific aberrant antigens 3,4 and must therefore evade immune detection to survive, 5 either by inducing immunosuppression 2 or deriving survival signals from tumor-infiltrating immune cells. 6 T cell-mediated antitumor immunity 4 requires recognition of cancer-associated antigen by the major histocompatibility complex (MHC), and appropriate costimulatory and repressive secondary signals arising from complex interactions with other immune, stromal, and tumor cells. Dysfunction of costimulation pathways may contribute to failed antitumor immunity.The B7 system (Table 1) is one of the most important secondary signaling mechanisms and is essential in maintaining the delicate balance between immune potency and suppression of autoimmunity. Potential therapeutic applications include immune-boosting adjuvants to conventional anticancer therapy, hematopoietic stem cell transplantation (HSCT), antitumor vaccines, bioengineered T cells as well as attenuation of graft-versus-host disease (GVHD). The B7 family is only one aspect of a complex signaling network (Figures 1 and 2) that comprises other immunoglobulin superfamily (IGSF) members, the tumor necrosis factor superfamily (TNFRSF), chemokines, cytokines, and adhesion molecules. However, based on a substantial evidence base and a growing therapeutic armory, the B7 family requires particular attention, as summarized in Table 2.7 The standardized approach to nomenclature is the cluster of differentiation (CD), which has not yet been applied to all members of the family. While many researchers are more familiar with their original names, which are still widely used in the literature, for the purposes of this review, the CD designation is used wherever possible. B7 founder members CD80, CD28, and CD152 (CTLA-4)The first B7 family member was a molecule discovered on activated, proliferative splenic B lymphocytes, 7 and termed B7 in an early nomenclature convention attributed to B cell-defining markers. Subsequent cloning and sequencing of the B7 gene revealed sequence homology with IGSF members and expression in a variety of lymphoid malignancies. 8 B7 was found to bind CD28, 9 an IGSF member on T cells, which augmented their activation. [10][11][12] Further molecular profiling identified a CD28 homologue, CD152 (cytolytic T cell-associated sequence-4 [CTLA-4]), 13 which mapped to the same chromosomal region as CD28 14 and bound B7 more potently. 15 The B7 signal blockade using a CTLA-4.Ig construct led to suppression of humoral 16 and cellmediated immune responses, 17 while transfection of immunogenic murine melanoma cell lines with B7 enhanced antitumor immunity, which could be abrogated by CTLA-4.Ig. 18 Initial experiments suggested that both anti-CD28 and anti-CTLA-4 monoclonal antibodies (mAbs) were T-cell activators, 19 but contrary evidence showing a suppressive role for CTLA-4 soon emerged 20,21 and was conclusively demonstrated in Ctla-4 Ϫ/Ϫ mice, which rapidl...

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“…More recent work has found that ICOS-L transfection of B16 tumor cells can promote enhanced antitumor immunity when such cells are irradiated and used for vaccination alongside anti-CTLA-4 treatment (8), and experiments with wild-type or ICOS À/À tumor-bearing mice have shown a requirement for ICOS signaling to support effective anti-CTLA-4 immunotherapy (9). Additional studies have found that recombinant ICOS-L can also promote antitumor immune responses (10,11), although the strong FcR-binding affinity of some of these molecules makes it difficult to distinguish whether they act through manipulation of ICOS signaling or direct antibody-dependent cellular cytotoxicity (ADCC)-based depletion of ICOS þ populations. However, ICOS can support both effector and regulatory populations (12), and in contrast to the above studies, clinical observations suggest that ICOS promotion of immunosuppressive T regs may impair tumor immunity (13), while human melanoma cells have been shown to support the induction of T regs in vitro through ICOS-L expression (14).…”

Section: Introductionmentioning

confidence: 99%

ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40–Mediated Tumor Rejection

et al. 2016

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ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumor immunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4 þ Foxp3À T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (T reg ), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8 þ T cells.We found that anti-OX40 efficacy, which is based on T reg depletion and to a large degree on CD4 þ effector T cell (T eff ) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both T eff and T reg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4 þ T cells by combining ICOS agonism and T reg depletion. Cancer Res; 76(13); 3684-9. Ó2016 AACR.

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Comparable in vivo efficacy of CD28/B7, ICOS/GL50, and ICOS/GL50B costimulatory pathways in murine tumor models: IFNγ-dependent enhancement of CTL priming, effector functions, and tumor specific memory CTL

Cited by 20 publications

References 37 publications

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

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

The role of B7 family molecules in hematologic malignancy

ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40–Mediated Tumor Rejection

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