T-cell agonists in cancer immunotherapy

Choi, Yeonjoo; Shi, Yi; Haymaker, Cara; Naing, Aung; Ciliberto, Gennaro; Hajjar, Joud

doi:10.1136/jitc-2020-000966

Cited by 84 publications

(52 citation statements)

References 110 publications

(137 reference statements)

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“…Notably, recent pre-clinical studies have shown that combination therapies aimed at enhancing such T-cell co-stimulating interactions improve anti-tumor immune responses even in low TMB and highly immuno-suppressive settings 33–38 . Currently, several clinical trials to assess the safety and efficacy of these combinations are in progress 39–42 .…”

Section: Discussionmentioning

confidence: 99%

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Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

Wang

Patkar

et al. 2021

Preprint

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The tumor microenvironment (TME) is a complex mixture of cell-types that interact with each other to affect tumor growth and clinical outcomes. To accelerate the discovery of such interactions, we developed CODEFACS (COnfident DEconvolution For All Cell Subsets), a deconvolution tool inferring cell-type-specific gene expression in each sample from bulk expression measurements, and LIRICS (LIgand Receptor Interactions between Cell Subsets), a supporting pipeline that analyzes the deconvolved gene expression from CODEFACS to identify clinically relevant ligand-receptor interactions between cell-types. Using 15 benchmark test datasets, we first demonstrate that CODEFACS substantially improves the ability to reconstruct cell-type-specific transcriptomes from individual bulk samples, compared to the state-of-the-art method, CIBERSORTx. Second, analyzing the TCGA, we uncover cell-cell interactions that specifically occur in TME of mismatch-repair-deficient tumors and are associated with their high response rates to anti-PD1 treatment. These results point to specific T-cell co-stimulating interactions that enhance immunotherapy responses in tumors independently of their mutation burden levels. Finally, using machine learning, we identify a subset of cell-cell interactions that predict patient response to anti-PD1 therapy in melanoma better than recently published bulk transcriptomics-based signatures. CODEFACS offers a way to study bulk cancer and normal transcriptomes at a cell type-specific resolution, complementing single-cell transcriptomics.

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Section: Discussionmentioning

confidence: 99%

“…3A interactions improve anti-tumor immune responses even in low TMB and highly immunosuppressive settings [32][33][34][35][36][37] . Currently, several clinical trials to assess the safety and efficacy of these combinations are in progress [38][39][40][41] .…”

Section: Tumors With Dna Mismatch Repair Deficiency Have Heightened Tmentioning

confidence: 99%

Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

Wang

Patkar

et al. 2021

Preprint

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“…Anti-CTLA-4 ICB, for instance, supports the induction phase of anti-tumor T cell responses, while ICB that targets the PD-1/PD-L1 axis serves mainly to maintain the effector phase of anti-tumor T cell responses. Therefore, the mixture of anti-CTLA-4 and anti-PD-1/PD-L1 therapies not only showed synergistic effects in pre-clinical models but also increased their efficacy compared to monotherapies in clinical settings such as in patients with metastatic melanoma and advanced renal cell carcinoma [ 26 , 27 ]. However, parallel with clinical effectiveness, there was an increase in the frequency of immune-related adverse events (irAE) with combinatorial ICB regimens [ 28 ].…”

Section: Current State Of Tumor Immunologymentioning

confidence: 99%

“…An alternative approach to mobilize tumor-specific T lymphocytes against cancer comprises the activation of co-stimulatory pathways by agonists [ 27 ]. The major co-stimulatory pathway, often referred to as the second signal of T lymphocyte activation, involves CD28 engagement by CD80/86.…”

Section: Current State Of Tumor Immunologymentioning

confidence: 99%

Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

Klepsch

Siegmund

Baier

2021

Cancers

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Additional therapeutic targets suitable for boosting anti-tumor effector responses have been found inside effector CD4+ and CD8+ T cells. It is likely that future treatment options will combine surface receptor and intracellular protein targets. Utilizing germline gene ablation as well as CRISPR/Cas9-mediated acute gene mutagenesis, the nuclear receptor NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) has been firmly characterized as such an intracellular immune checkpoint in effector T cells. Targeting this receptor appears to be a strategy for improving anti-tumor immunotherapy responses, especially in combination with CTLA-4 and PD-1. Current preclinical experimental knowledge firmly validates the immune checkpoint function of NR2F6 in murine tumor models, which provides a promising perspective for immunotherapy regimens in humans in the near future. While the clinical focus remains on the B7/CD28 family members, protein candidate targets such as NR2F6 are now being investigated in laboratories around the world and in R&D companies. Such an alternative therapeutic approach, if demonstrated to be successful, could supplement the existing therapeutic models and significantly increase response rates of cancer patients and/or expand the reach of immune therapy regimens to include a wider range of cancer entities. In this perspective review, the role of NR2F6 as an emerging and druggable target in immuno-oncology research will be discussed, with special emphasis on the unique potential of NR2F6 and its critical and non-redundant role in both immune and tumor cells.

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“…Full T cell activation requires three key signals: engagement of T cell receptors by antigen peptide-bound major histocompatibility complex, ligation of co-stimulatory molecules, and support from cytokines [1]. In addition, recent studies have stressed a cardinal role of co-inhibitory molecules in regulating excessive T cell activation [2][3][4][5]. There are several co-stimulatory and co-inhibitory molecules, also known as immune checkpoint molecules (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

OX40L–OX40 Signaling in Atopic Dermatitis

Furue

Furue²

2021

JCM

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OX40 is one of the co-stimulatory molecules expressed on T cells, and it is engaged by OX40L, primarily expressed on professional antigen-presenting cells such as dendritic cells. The OX40L–OX40 axis is involved in the sustained activation and expansion of effector T and effector memory T cells, but it is not active in naïve and resting memory T cells. Ligation of OX40 by OX40L accelerates both T helper 1 (Th1) and T helper 2 (Th2) effector cell differentiation. Recent therapeutic success in clinical trials highlights the importance of the OX40L–OX40 axis as a promising target for the treatment of atopic dermatitis.

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T-cell agonists in cancer immunotherapy

Cited by 84 publications

References 110 publications

Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

Deconvolving clinically relevant cellular immune crosstalk from bulk gene expression using CODEFACS and LIRICS

Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6

OX40L–OX40 Signaling in Atopic Dermatitis

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