Targeting TBK1 to overcome resistance to cancer immunotherapy

Sun, Yi; Revach, Or‐Yam; Anderson, Seth; Kessler, Emily; Wolfe, Clara; Jenney, Anne; Mills, Caitlin E.; Robitschek, Emily; Davis, Thomas; Kim, Sarah; Fu, Amina; Ma, Xiang; Gwee, Jia; Tiwari, Payal; Du, Peter; Sindurakar, Princy; Tian, Jiajun; Mehta, Arnav; Schneider, Alexis M.; Yizhak, Keren; Sade-Feldman, Moshe; LaSalle, Thomas J.; Sharova, Tatyana; Xie, Hongyan; Liu, Shuming; Michaud, William A.; Saad-Beretta, Rodrigo; Yates, Kathleen B.; Iracheta-Vellve, Arvin; Spetz, Johan; Qin, Xingping; Sarosiek, Kristopher A.; Zhang, Gao; Kim, Jong Wook; Su, Mack Y.; Cicerchia, Angelina M.; Rasmussen, Martin Q.; Klempner, Samuel J.; Juric, Dejan; Pai, Sara I.; Miller, David M.; Giobbie‐Hurder, Anita; Chen, Jonathan; Pelka, Karin; Frederick, Dennie T.; Stinson, Susanna; Ivanova, Elena; Aref, Amir Reza; Paweletz, Cloud P.; Barbie, David A.; Sen, Debattama R.; Fisher, David E.; Corcoran, Ryan B.; Hacohen, Nir; Sorger, Peter K.; Flaherty, Keith T.; Boland, Genevieve M.; Manguso, Robert T.; Jenkins, Russell W.

doi:10.1038/s41586-023-05704-6

Cited by 68 publications

(39 citation statements)

References 64 publications

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“…Analysis of B16-ova scRNAseq. scRNA-seq data for CD45+ tumour-infiltrating immune cells isolated from C57BL/6J mice inoculated with subcutaneous B16-ova tumours treated with ICB were previously described 21 (Gene Expression Omnibus (GEO): GSE217160). In this analysis, data were subset to only include cells isolated from control (vehicle/IgG-treated) and anti-PD-1 (vehicle/anti-PD-1-treated) groups.…”

Section: Analysis Of B16 Scrnaseq (Gene Expression Omnibus (Geo): Gse...mentioning

confidence: 99%

“…In this analysis, data were subset to only include cells isolated from control (vehicle/IgG-treated) and anti-PD-1 (vehicle/anti-PD-1-treated) groups. Quality-control, filtering, and normalisation were performed as previously described 21 . Additional analysis and plotting were performed using Scanpy (v.1.9.3).…”

Section: Analysis Of B16 Scrnaseq (Gene Expression Omnibus (Geo): Gse...mentioning

confidence: 99%

“…a, Tumour type, tissue source (location), gender, age, clinical response, PDOTS response data, tumour mutational burden (TMB), and associated tumour mutational profile for specimens used for PDOTS profiling (n=30; samples ordered by response to dual PD-1/CD38 blockade). PDOTS response parameters defined as previously described 21 : responder (reduction >30% compared to control), partial responder (<30% reduction and <20% growth compared to control), and non-responder (>20% growth compared to control). (n=6 biological replicates; 2 independent CAR-T donors; 2-sided unpaired t-test).…”

Section: Analysis Of Human Tumours and Human T Cells By Flow Cytometrymentioning

confidence: 99%

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Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Revach,

Cicerchia,

Shorer

et al. 2024

Preprint

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A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

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Section: Analysis Of B16 Scrnaseq (Gene Expression Omnibus (Geo): Gse...mentioning

confidence: 99%

Section: Analysis Of B16 Scrnaseq (Gene Expression Omnibus (Geo): Gse...mentioning

confidence: 99%

Section: Analysis Of Human Tumours and Human T Cells By Flow Cytometrymentioning

confidence: 99%

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Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Revach,

Cicerchia,

Shorer

et al. 2024

Preprint

Self Cite

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“…By combining PDO and humanized mouse techniques, the investigators constructed a new model of spontaneous multi-organ metastasis from microsatellite instability-H CRC and also provided empirical evidence for a key role of B cells in generating site-dependent anti-tumor immunity after anti-CTLA-4 treatment( 62 ). Researchers also demonstrated using a patient-derived organotypic tumor spheroids (PDOTS) and a matched PDO drug screening platform that inhibition of innate immune kinase TANK-binding kinase 1 coupled with PD-1 blockade was an effective strategy for overcoming tumor immunotherapy resistance ( 63 ). In addition, the investigators established a glioblastoma (GBO)-related organoid biobank for individualized therapeutic screening.…”

Section: Pdx and Pdo Models In The Discovery Of Traditional Tumor Imm...mentioning

confidence: 99%

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy

Zhang

Zheng

2023

Front. Oncol.

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In addition to the rapid development of immune checkpoint inhibitors, there has also been a surge in the development of self-assembly immunotherapy drugs. Based on the immune target, traditional tumor immunotherapy drugs are classified into five categories, namely immune checkpoint inhibitors, direct immune modulators, adoptive cell therapy, oncolytic viruses, and cancer vaccines. Additionally, the emergence of self-assembled drugs with improved precision and environmental sensitivity offers a promising innovation approach to tumor immunotherapy. Despite rapid advances in tumor immunotherapy drug development, all candidate drugs require preclinical evaluation for safety and efficacy, and conventional evaluations are primarily conducted using two-dimensional cell lines and animal models, an approach that may be unsuitable for immunotherapy drugs. The patient-derived xenograft and organoids models, however, maintain the heterogeneity and immunity of the pathological tumor heterogeneity.

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“…PPARγ-agonists, such as pioglitazone, reprogramme the metabolism and inflammatory response of microsatellite-stable (MSS) CRC cells and increase their PD-L1 expression, sensitising these seemingly resistant organoids to ICI [ 139 ]. Targeting TBK1, a kinase with multifaceted functions in innate immunity and cell proliferation, also enhances ICI response, as seen in PDOTS of multiple cancers [ 140 ].…”

Section: Translational Immuno-oncology Research With Organoidsmentioning

confidence: 99%

Organoids as an Enabler of Precision Immuno-Oncology

Zhao

Fong

Seow

et al. 2023

Cells

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Since the dawn of the past century, landmark discoveries in cell-mediated immunity have led to a greater understanding of the innate and adaptive immune systems and revolutionised the treatment of countless diseases, including cancer. Today, precision immuno-oncology (I/O) involves not only targeting immune checkpoints that inhibit T-cell immunity but also harnessing immune cell therapies. The limited efficacy in some cancers results mainly from a complex tumour microenvironment (TME) that, in addition to adaptive immune cells, comprises innate myeloid and lymphoid cells, cancer-associated fibroblasts, and the tumour vasculature that contribute towards immune evasion. As the complexity of TME has called for more sophisticated human-based tumour models, organoids have allowed the dynamic study of spatiotemporal interactions between tumour cells and individual TME cell types. Here, we discuss how organoids can study the TME across cancers and how these features may improve precision I/O. We outline the approaches to preserve or recapitulate the TME in tumour organoids and discuss their potential, advantages, and limitations. We will discuss future directions of organoid research in understanding cancer immunology in-depth and identifying novel I/O targets and treatment strategies.

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Targeting TBK1 to overcome resistance to cancer immunotherapy

Cited by 68 publications

References 64 publications

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy

Organoids as an Enabler of Precision Immuno-Oncology

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