Harnessing cytokines and chemokines for cancer therapy

Propper, David; Balkwill, Frances R.

doi:10.1038/s41571-021-00588-9

Cited by 489 publications

(336 citation statements)

References 230 publications

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“…Targeting SMPs such as PD1/PD-L1 and CTLA4 has been commonly used in the clinic, including in the treatment of LSCC [ 19 – 22 ]. Using CAR T cells with cancer-specific SMPs or coupling SMPs' antibodies with chemotherapeutic agents is also developing rapidly [ 23 – 25 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Significant Secreted or Membrane-Located Proteins in Laryngeal Squamous Cell Carcinoma

et al. 2022

Journal of Immunology Research

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Background. This study is aimed at investigating the expressions and prognostic values of secreted or membrane-located proteins (SMPs) in laryngeal squamous cell carcinoma (LSCC). The correlations between the expressions of SMPs and immune cells’ infiltrations were also investigated. Methods. The expression data of normal laryngeal and LSCC samples were obtained from the TCGA and GEO datasets. The differentially expressed SMPs were identified, and their prognostic values were analyzed. The biological functions of differentially expressed and worse-survival-related SMPs were explored. LASSO regression, Cox multivariate analysis, and nomogram were used to construct a model to predict the survival. Then, the infiltrations of the 24 immune cell populations were calculated using the GSVA method, and the correlations between the expression of SMPs and the immune infiltration were investigated. Results. 122 samples (12 normal and 120 LSCC) of the TCGA database and 114 samples (57 normal and 57 LSCC) of GSE127165 were included. We identified that 138 SMPs were significantly upregulated in LSCC samples of both the TCGA and GEO datasets, among which 52 SMPs were significantly correlated with worse survival. GO and KEGG analyses revealed those 52 SMPs significantly participate in tumor microenvironment and immune cells’ communication. Nine of 52 SMPs (ABCC5, ATP1B3, CLEC11A, FLNA, FSTL3, MMP1, NME1, OAS3, and PHLDB2) were included in the nomogram to effectively and accurately predict the LSCC patients’ survival. The expressions of most SMPs, such as MMP1 and FSTL3, were significantly positively correlated with the immune infiltration of LSCC. Conclusions. In this study, the expression, prognostic values, and correlations with immune infiltration of SMPs were analyzed in LSCC samples. Our analyses identified several significant SMPs differentially expressed between normal laryngeal and LSCC samples, correlated with worse survival, and related to the immune infiltration.

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Section: Discussionmentioning

confidence: 99%

Identification of Significant Secreted or Membrane-Located Proteins in Laryngeal Squamous Cell Carcinoma

et al. 2022

Journal of Immunology Research

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“…While these data suggest cancer patients might benefit from targeting myeloid cells, current clinical results also highlight the need to improve this strategy. Promising targets for myeloid reprograming include targeting CD40, CD163, CD47/SIRPa, MERTK, TLRs and others (1,48,54). Here-in we investigate CD11b-agonists as a novel myeloid reprograming approach.…”

Section: Discussionmentioning

confidence: 99%

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Liu

Hogg

Zuo

et al. 2022

Preprint

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Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them.

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“…The IFNIs exert their anti-proliferative, anti-tumor, anti-angiogenic, and immunomodulatory properties by activating the Janus kinase signal transducer and activator of transcription signals via the common type-I IFN receptor (IFNAR) ( 23 , 24 ). The IFNα is still widely used in the treatment of chronic viral infections, hematological malignancies, and certain cancers ( 25 ), whereas IFNβ preparations are recommended for multiple isoforms of MS ( 5 , 6 ). Opposing the beneficial actions of IFNI treatment, IFNI has gradually been recognized as a pro-inflammatory molecule that may not only unmask and aggravate underlying autoimmune processes, but also induce de novo autoimmune disorders, such as type-I diabetes, vitiligo, SLE, Sjögren syndrome, and autoimmune thyroid disease ( 26 – 28 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Interferon-Alpha-Induced Neuromyelitis Optica Spectrum Disorder

Rao

Sun

et al. 2022

Front. Neurol.

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Background and ObjectivesTo describe a new case of neuromyelitis optica spectrum disorder (NMOSD) induced by the administration of interferon-alpha (IFNα) and to raise awareness of this rare drug-induced disease of IFNα treatment.MethodsA single case study and comprehensive literature review of eight cases.ResultsA 24-year-old man was diagnosed with cerebral venous thrombosis and essential thrombocythemia. He had been undergoing IFNα treatment (IFNα-2b, 3 million IU per day) without any side effects for 18 months, at which point the patient developed persistent hiccups, nausea, urinary retention, and numbness. Spinal magnetic resonance imaging revealed a longitudinal abnormality extending from the medulla to the entire spinal cord. The patient was positive for anti-aquaporin-4 antibody (AQP4-IgG) in both the serum and cerebrospinal fluid (CSF), which confirmed the diagnosis of NMOSD. Thus, recombinant IFNα-2b was suspended immediately. Because his condition did not improve after 6-day treatment of methylprednisolone pulse therapy (1,000 mg for 3 days, then 500 mg for 3 days), intravenous immunoglobulin (0.4 g/kg/day for 5 days) was administered. The patient gradually improved. Low-dose prednisolone and mycophenolate mofetil were subsequently administered as a long-term treatment. The patient was discharged with subtle limb numbness and their expanded disability status score (EDSS) was 1. At the 1-year follow-up, the patient had not relapsed and tested negative for AQP4-IgG. We further identified the eight patients with IFNα-induced NMOSD. The median onset age was 59 years, and the median time of IFNα exposure was 18 months. Optic neuritis was the most common initial symptom (five, 55.6%), followed by myelitis in three patients and area postrema syndrome in one patient. More than half (five, 55.6%) of the patients were monophasic. After IFNα discontinuation and immunotherapy, most (seven, 77.8%) patients remained relapse-free. However, only one patient was free of sequelae.ConclusionThis study highlights the potential pathogenic risk of NMOSD of IFNα treatment. Given the high disability rates of this rare drug-induced disease, it is crucial to monitor the early manifestations of NMOSD during IFNα treatment.

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Harnessing cytokines and chemokines for cancer therapy

Cited by 489 publications

References 230 publications

Identification of Significant Secreted or Membrane-Located Proteins in Laryngeal Squamous Cell Carcinoma

Identification of Significant Secreted or Membrane-Located Proteins in Laryngeal Squamous Cell Carcinoma

Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients

Case Report: Interferon-Alpha-Induced Neuromyelitis Optica Spectrum Disorder

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