The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade

Cucolo, Lisa; Chen, Qingzhou; Qiu, Jingya; Yu, Yongjun; Klapholz, Max; Budinich, Krista A.; Zhang, Zhaojun; Shao, Yue; Brodsky, Igor E.; Jordan, Martha S.; Gilliland, D. Gary; Zhang, Nancy R.; Shi, Junwei; Minn, Andy J.

doi:10.1016/j.immuni.2022.03.007

Cited by 56 publications

(38 citation statements)

References 64 publications

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“…These results suggest that the transcriptional profiles revealed in scCRISPR immune screens can be used to outline the phenotypic landscape of targeting tumor intrinsic factors in response to cancer immunotherapy and predict therapeutic potentials of new IO combinations. More importantly, our analysis of interaction effects not only showed that inhibiting Prmt1 or Ripk1 can modulate activities of antigen presentation and interferon signaling pathways, which were further validated by recently published studies ( 10 , 44 , 45 ), but also found a series of pathways and genes whose immunological function remains unclear. Given that the interaction effects of genetic perturbation and immunotherapy cannot be easily evaluated by conventional molecular methods, scCRISPR immune screens have a great potential to identify novel tumor immune evasion mechanisms.…”

Section: Discussionsupporting

confidence: 75%

Single-cell CRISPR immune screens reveal immunological roles of tumor intrinsic factors

Hou

Liang

et al. 2022

NAR Cancer

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Genetic screens are widely exploited to develop novel therapeutic approaches for cancer treatment. With recent advances in single-cell technology, single-cell CRISPR screen (scCRISPR) platforms provide opportunities for target validation and mechanistic studies in a high-throughput manner. Here, we aim to establish scCRISPR platforms which are suitable for immune-related screens involving multiple cell types. We integrated two scCRISPR platforms, namely Perturb-seq and CROP-seq, with both in vitro and in vivo immune screens. By leveraging previously generated resources, we optimized experimental conditions and data analysis pipelines to achieve better consistency between results from high-throughput and individual validations. Furthermore, we evaluated the performance of scCRISPR immune screens in determining underlying mechanisms of tumor intrinsic immune regulation. Our results showed that scCRISPR platforms can simultaneously characterize gene expression profiles and perturbation effects present in individual cells in different immune screen conditions. Results from scCRISPR immune screens also predict transcriptional phenotype associated with clinical responses to cancer immunotherapy. More importantly, scCRISPR screen platforms reveal the interactive relationship between targeting tumor intrinsic factors and T cell-mediated antitumor immune response which cannot be easily assessed by bulk RNA-seq. Collectively, scCRISPR immune screens provide scalable and reliable platforms to elucidate molecular determinants of tumor immune resistance.

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Section: Discussionsupporting

confidence: 75%

Single-cell CRISPR immune screens reveal immunological roles of tumor intrinsic factors

Hou

Liang

et al. 2022

NAR Cancer

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“…RIPK1 K376R mutants showed low pro-tumorigenic chemokine generation. Additionally, they showed sensitivity to TNF-induced cell death (39). This suggests that RIPK1 polyubiquitin regulation could provide an excellent target for cancer therapy.…”

Section: Discussionmentioning

confidence: 94%

Tob negatively regulates NF-κB activation in breast cancer through its association with the TNF receptor complex.

Yamamoto

Tokumasu

Sato

et al. 2023

Preprint

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NF-κB mediates transcriptional regulation crucial to many biological functions, and elevated NF-κB activity leads to autoimmune and inflammatory diseases, as well as cancer. Since highly aggressive breast cancers have few therapeutic molecular targets, clarification of key molecular mechanisms of NF-κB signaling would facilitate development of more effective therapy. In this report, we show that Tob, a member of the Tob/BTG family of antiproliferative proteins, acts as a negative regulator of the NF-κB signal in breast cancer. Studies with 35 human breast cancer cell lines reveal that Tob expression is negatively correlated with NF-κB activity. Analysis of The Cancer Genome Atlas (TCGA) database of clinical samples reveals an inverse correlation between Tob expression and NF-κB activity. Tob2, another member of the Tob/BTG family, shows no such negative correlations. Furthermore, in TNF-α treated cells, Tob associates with TNF receptor complex I to suppress polyubiquitylation of RIPK1, which results in repression of NF-kB activity. Therefore, Tob functions as a negative regulator of the NF-κB pathway and may serve as a therapeutic target for aggressive breast cancer.

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“…The models of canonical CT26 colon cancer and B16 melanoma are relatively sensitive to immune checkpoint blockade. [ 46 ] Thus, in this study, these two murine models were developed and the tumor‐bearing was injected with EcN‐αPD1‐S1 once tumor volume reached ≈200 mm 3 . PBS and equivalent αPD1, S1 protein, and EcN to dressed bacteria were dosed as controls.…”

Section: Resultsmentioning

confidence: 99%

Dressing Bacteria With a Hybrid Immunoactive Nanosurface to Elicit Dual Anticancer and Antiviral Immunity

et al. 2023

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Approaches capable of simultaneously treating cancer and protecting susceptible patients from lethal infections such as coronavirus disease 2019, are highly desirable but prove to be difficult. Here, dressing bacteria with a hybrid immunoactive nanosurface is reported to elicit dual anticancer and antiviral immunity. A combination of a checkpoint blocking antibody and a virus‐specific antigen is covalently conjugated to polydopamine nanoparticles, which can be anchored onto bacterial surface, by a one‐step in situ polymerization of dopamine under a cell‐friendly condition. By virtue of the ability to colonize and penetrate deep tumor tissue, dressed bacteria enable sustained release and expanded exposure of carried immunoactivators to stimulate immune cells. In addition to a carrier role, bacteria are able to further provoke innate immunity due to the native immunogenicity of the pathogen‐associated molecular patterns. Immunization with dressed bacteria promotes the maturation, and activation of antigen‐presenting cells, which induces robust humoral and cellular immune responses in tumor‐bearing mice. As evidenced by efficient production of viral‐antigen‐specific immunoglobulin G antibody in serum and significantly suppressed tumor growth in different models, dressing bacteria with a hybrid immunoactive nanosurface paves an avenue to prepare next‐generation therapeutics for synergistic treatment and prevention.

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The interferon-stimulated gene RIPK1 regulates cancer cell intrinsic and extrinsic resistance to immune checkpoint blockade

Cited by 56 publications

References 64 publications

Single-cell CRISPR immune screens reveal immunological roles of tumor intrinsic factors

Single-cell CRISPR immune screens reveal immunological roles of tumor intrinsic factors

Tob negatively regulates NF-κB activation in breast cancer through its association with the TNF receptor complex.

Dressing Bacteria With a Hybrid Immunoactive Nanosurface to Elicit Dual Anticancer and Antiviral Immunity

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