An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression

Sainson, Richard C.A.; Thotakura, Anil K.; Kosmač, Miha; Borhis, Gwenoline; Parveen, Nahida; Kimber, Rachael; Carvalho, Joana; Henderson, Simon J.; Pryke, Kerstin; Okell, Tracey; O’Leary, Siobhan; Ball, Stuart; Krinks, Cassie Van; Gamand, Lauriane; Taggart, Emma; Pring, Eleanor; Ali, Hanif; Craig, Hannah; Wong, Vivian W.Y.; Liang, Qi; Rowlands, Robert J.; Lecointre, Morgane; Campbell, Jamie I. D.; Kirby, Ian; Melvin, David; Germaschewski, Volker; Oelmann, Elisabeth; Quaratino, Sonia; McCourt, Matthew

doi:10.1158/2326-6066.cir-20-0034

Cited by 26 publications

(17 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have shown that the stimulation of these receptors reduces the immunosuppressive function of Tregs, leading to the activation of effector T cells. 132 133 Antibodies that act as agonists of OX40, such as MEDI6469 134 (NCT02274155), GITR, such as MK-4166 135 (NCT02132754), and ICOS, such as KY1044 136 (NCT03829501), are currently being investigated.…”

Section: Targeting Chemokine Receptors and Immune Checkpoint Molecules On Tregsmentioning

confidence: 99%

Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies

Nishikawa

Koyama

2021

J Immunother Cancer

163

View full text Add to dashboard Cite

With the broad application of cancer immunotherapies such as immune checkpoint inhibitors in multiple cancer types, the immunological landscape in the tumor microenvironment (TME) has become enormously important for determining the optimal cancer treatment. Tumors can be immunologically divided into two categories: inflamed and non-inflamed based on the extent of immune cell infiltration and their activation status. In general, immunotherapies are preferable for the inflamed tumors than for non-inflamed tumors. Regulatory T cells (Tregs), an immunosuppressive subset of CD4+ T cells, play an essential role in maintaining self-tolerance and immunological homeostasis. In tumor immunity, Tregs compromise immune surveillance against cancer in healthy individuals and impair the antitumor immune response in tumor-bearing hosts. Tregs, therefore, accelerate immune evasion by tumor cells, leading to tumor development and progression in various types of cancer. Therefore, Tregs are considered to be a crucial therapeutic target for cancer immunotherapy. Abundant Tregs are observed in the TME in many types of cancer, both in inflamed and non-inflamed tumors. Diverse mechanisms of Treg accumulation, activation, and survival in the TME have been uncovered for different tumor types, indicating the importance of understanding the mechanism of Treg infiltration in each patient when selecting the optimal Treg-targeted therapy. Here, we review recent advances in the understanding of mechanisms leading to Treg abundance in the TME to optimize Treg-targeted therapy. Furthermore, in addition to the conventional strategies targeting cell surface molecules predominantly expressed by Tregs, reagents targeting molecules and signaling pathways specifically employed by Tregs for infiltration, activation, and survival in each tumor type are illustrated as novel Treg-targeted therapies. The effectiveness of immune precision therapy depends on conditions in the TME of each cancer patient.

show abstract

Section: Targeting Chemokine Receptors and Immune Checkpoint Molecules On Tregsmentioning

confidence: 99%

Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies

Nishikawa

Koyama

2021

J Immunother Cancer

163

View full text Add to dashboard Cite

show abstract

“…KY1044, a fully human IgG1 antibody bounding to ICOS, induced sustained depletion of ICOS + Treg cells and increased the intra-tumoral Teff/Treg ratio. This KY1044 monotherapy has been demonstrated to improve the anti-PD-L1 efficacy in cancers [ 373 ]. Tregs-targeted therapy combined with ICIs can attenuate Treg-mediated drug resistance and increase tumor cell sensitivity to treatment, thereby promoting tumor regression.…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets

et al. 2022

View full text Add to dashboard Cite

Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients are refractory or resistant to these therapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Thus, targeting these immunosuppressive cells and the related signals is the promising therapy to improve the efficacy of immunotherapies and reverse the immune resistance. However, even with certain success in preclinical studies or in some specific types of cancer, large perspectives are unknown for these immunosuppressive cells, and the related therapies have undesirable outcomes for clinical patients. In this review, we comprehensively summarized the phenotype, function, and potential therapeutic targets of these immunosuppressive cells in the tumor microenvironment.

show abstract

“…Compared to Teffs, Tregs generally express a higher level of ICOS. In preclinical models, the differential expression of ICOS on Tregs and Teffs was exploited, and the anti-ICOS agonistic antibody was demonstrated to induce sustained depletion of ICOShigh Tregs and activate ICOS-low Teffs, resulting in an increase in Teffs/Tregs ratio in the TME, further enhancing the antitumor efficacy of the ICIs [17]. At least 6 ICOS antibodies have been tested in clinical trials: JTX-2011, GSK-3359609, MEDI-570, BMS-986225, XmAb23104, and KY1044 [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

“…Formalin-fixed, paraffin-embedded tissue sections (5-µm thickness) of each patient were retrieved from the archived tissues of the Department of Pathology, NTUH. A modified, sequential multiplex IHC assay was performed to evaluate ICOS and Foxp3 expression by procedures as described previously [17]. Briefly, tissue slides were deparaffinized, rehydrated, and autoclaved in citrate buffer (pH 6.0) for 10 min using a decloaking chamber for antigen retrieval, followed by blocking with hydrogen peroxide and then Background Sniper (BioCare Medical) to reduce nonspecific background staining.…”

Section: Ihc Stainingmentioning

confidence: 99%

“…Although ICOS is an important co-stimulatory receptor on effector T cells (Teffs), regulatory T cells (Tregs) generally express higher levels of ICOS than Teffs. In preclinical models, the anti-ICOS KY1044 was shown to stimulate ICOS-low Teffs and preferentially deplete ICOS-high Tregs via antibody-dependent cellular cytotoxicity, resulting in an increase in Teffs/Tregs ratio in the tumor microenvironment (TME) and an enhanced antitumor immune response [17].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis

Deantonio

Palu

et al. 2022

Oncology

Self Cite

View full text Add to dashboard Cite

Introduction: Inducible co-stimulator (ICOS), an important co-stimulatory receptors on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC). Methods: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed. Results: A total of 142 patients (male: female= 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low AFP level (<20 ng/ml) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS＋Foxp3＋ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p<0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS＋Foxp3＋ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS＋Foxp3＋ cells and ICOS＋Foxp3－ cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p=0.030), suggesting active immunosuppression of ICOS＋ Tregs on ICOS＋ Teffs. Conclusion: An increased abundance of ICOS＋ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC.

show abstract

An Antibody Targeting ICOS Increases Intratumoral Cytotoxic to Regulatory T-cell Ratio and Induces Tumor Regression

Abstract: An antibody targeting ICOS increases intratumoral cytotoxic to regulatory T cell ratio and induces tumor regression Anti-tumour activity triggered by an anti-ICOS antibody

Cited by 26 publications

References 59 publications

Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies

Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies

Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets

ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis

Contact Info

Product

Resources

About