Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

Weulersse, Marianne; Asrir, Assia; Pichler, Andrea; Lemaître, L; Braun, Matthias; Carrié, Nadège; Joubert, Marie-Véronique; Moine, Marie Le; Souto, Laura Do; Gaud, Guillaume; Das, Indrajit; Brauns, Elisa; Scarlata, Clara-Maria; Morandi, Elena; Sundarrajan, Ashmitha; Cuisinier, Marine; Buisson, Laure; Mahéo, Sabrina; Kassem, Sahar; Agesta, Arantxa; Pérès, Michaël; Verhoeyen, Els; Martinez, Alejandra; Mazières, Julien; Dupré, Loı̈c; Gossye, Thomas; Pancaldi, Véra; Guillerey, Camille; Ayyoub, Maha; Dejean, Anne S.; Saoudi, Abdelhadi; Goriely, Stanislas; Avet‐Loiseau, Hervé; Bald, Tobias; Smyth, Mark J.; Martinet, Ludovic

doi:10.1016/j.immuni.2020.09.006

Cited by 99 publications

(116 citation statements)

References 82 publications

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“…Taken together the results implicate derepression of DNAM-1 co-stimulatory signaling in response to PD-1 inhibition, similar to the role that has been proposed for CD28 involvement in an anti-PD-1 response (101). Another study has similarly shown that DNAM-1 is required for PD-1 blockade anti-tumor activity in pre-clinical mouse models (102). In accordance with these results, DNAM expression on TILs was shown to correlate positively with the response to PD-1 blockade in melanoma patients (103).…”

Section: Pd-1: a Player In The Dnam-1 Axis?supporting

confidence: 81%

Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis

Alteber

Kotturi²,

Whelan³

et al. 2021

Cancer Discovery

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are co-first authors of this review Disclosure of Potential Conflicts of Interest Z. Alteber, E. Weyl and E. Ophir are Employees of Compugen Ltd. with stock options. M. F. Kotturi is Former Compugen Ltd employee with company stock options; current employee with company stock options at IGM Biosciences Inc; S. Whelan is Former employee of Compugen Ltd. Currently an employee and equity holder of Nurix Therapeutics S. Gungluy has no conflict of interest. D.M. Pardoll reports receiving commercial research funding from Bristol-Myers Squibb, Compugen, and AstraZeneca; has ownership interest in Aduro Biotech, DNAtrix, Dracen, Enara, Five Prime Therapeutics, Tizona, Trieza, and WindMil; and is a consultant/ advisory board member for Amgen, Bayer, FLX Bio, Immunomic, Janssen, Merck, Rock Springs Capitol, and Tizona. J. Hunter is Former Compugen Ltd employee with company stock options; current employee and equity holder of Keyhole Therapeutics Inc

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Section: Pd-1: a Player In The Dnam-1 Axis?supporting

confidence: 81%

Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis

Alteber

Kotturi²,

Whelan³

et al. 2021

Cancer Discovery

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show abstract

“…CNV analysis showed that genes related to chemokines, cytokines, and immune response receptors, including CD226, CXCL9, CXCL11, and IL2, were deleted to varying degrees in the C3 subtype. Moreover, the low expression of these genes was significantly related to poor prognosis in patients with OC, and we found that they had previously been validated as associated with tumor immune response and immunotherapeutic efficacy (47)(48)(49).…”

Section: Discussionmentioning

confidence: 64%

Comprehensive Landscape of Ovarian Cancer Immune Microenvironment Based on Integrated Multi-Omics Analysis

et al. 2021

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Epithelial ovarian cancer has a low response rate to immunotherapy and a complex immune microenvironment that regulates its treatment outcomes. Understanding the immune microenvironment and its molecular basis is of great clinical significance in the effort to improve immunotherapy response and outcomes. To determine the characteristics of the immune microenvironment in ovarian cancer, we stratified ovarian cancer patients into three immune subtypes (C1, C2, and C3) using immune-related genes based on gene expression data from The Cancer Genome Atlas and found that these three subtypes had significant differences in immune characteristics and prognosis. Methylation and copy number variant analysis showed that the immune checkpoint genes that influenced immune response were significantly hypermethylated and highly deleted in the immunosuppressive C3 subtype, suggesting that epigenetic therapy may be able to reverse the efficacy of immunotherapy. In addition, the mutation frequencies of BRCA2 and CDK12 were significantly higher in the C2 subtype than in the other two subtypes, suggesting that mutation of DNA repair-related genes significantly affects the prognosis of ovarian cancer patients. Our study further elucidated the molecular characteristics of the immune microenvironment of ovarian cancer, which providing an effective hierarchical method for the immunotherapy of ovarian cancer patients, and has clinical relevance to the design of new immunotherapies and a reasonable combination strategies.

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“…Most recent studies on CD226 downregulation by EOMES and CBL-B and its impact on antitumor activity of CD8 + T cells also highlight the crucial role of CD226 for effective cancer immunotherapy (26,74).…”

Section: Cd226mentioning

confidence: 99%

“…A recent study using preclinical mouse models reported that inhibiting CD112R promotes an antitumor immune response by restoring T-cell activities. Pmel-1 CD8 + T cells isolated from Pmel-1 TCR-CD112Rdeficient mice show augmented effector responses, including CD107 expression and effector cytokine production upon gp100 [25][26][27][28][29][30][31][32][33] stimulation and subsequent co-culture with B16/F10 tumor cells expressing mhgp100 and Nectin-2 (85). Consistent with the in vitro results, MC38 tumor growth was decreased in http://bmbreports.org Fig.…”

Section: Cd112rmentioning

confidence: 99%

Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy

Jin

Park

2021

BMB Rep.

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Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are a group of immunoglobulin superfamily receptors that interact with Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals upon binding their cognate ligands to the immune cells. The integrated signals formed by their complex interactions contribute to regu-lating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.

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Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8+ T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy

Cited by 99 publications

References 82 publications

Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis

Therapeutic Targeting of Checkpoint Receptors within the DNAM1 Axis

Comprehensive Landscape of Ovarian Cancer Immune Microenvironment Based on Integrated Multi-Omics Analysis

Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy

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