Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer

Emmons, Tiffany R.; Giridharan, Thejaswini; Singel, Kelly L.; Khan, Atiya; Ricciuti, Jason; Howard, Kaitlyn; Toro, Stephanie L. Silva-Del; Debreceni, Ivy L.; Aarts, Cathelijn E.M.; Brouwer, Mieke C.; Suzuki, Sora; Kuijpers, Taco W.; Jongerius, Ilse; Allen, Lee‐Ann H.; Ferreira, Viviana P.; Schubart, Anna; Sellner, Holger; Eder, Joerg; Holland, Steven M.; Ram, Sanjay; Lederer, James A.; Eng, Kevin H.; Moysich, Kirsten B.; Odunsi, Kunle; Yaffe, Michael B.; Zsiros, Emese; Segal, Brahm H.

doi:10.1158/2326-6066.cir-20-0922

Cited by 28 publications

(31 citation statements)

References 66 publications

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“…As CNTN1 does not vary with age, abnormal CNTN1 levels were defined as below the 5th percentile of values in HCs (appendix 1) [ 17 ]. Complement activation products of C3 (C3b, C3bi and C3c) and C4 (C4b, C4bi, C4c), collectively referred to as C3b/c and C4b/c, respectively, were measured in serum of a subgroup of PN patients by enzyme-linked immunosorbent assay (ELISA) as described previously [ 19 ]. Normal reference values were measured in a pool of HCs as well as individual donors and maximum C3b/c and C4b/c levels in HCs were used as cutoff values.…”

Section: Methodsmentioning

confidence: 99%

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

et al. 2022

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Introduction In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN. Methods In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström’s Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN). Results NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients. Conclusion Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up.

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Section: Methodsmentioning

confidence: 99%

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

et al. 2022

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“…We found that clinical outcomes were associated with CAR T-cell differential vector integration events. Interestingly, in non-responders, more integration events were found in genes mainly involved in neutrophil activation, which may mediate immune suppression activity [ 44 , 45 ]. These results suggest that further study of differential integration events could reveal additional useful predictive markers for clinical outcomes, recognizing the limitation, however, that these analyses are rarely done in real-time and are often assessed after patients are treated.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products

et al. 2022

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Background Clinical CAR T-cell therapy using integrating vector systems represents a promising approach for the treatment of hematological malignancies. Lentiviral and γ-retroviral vectors are the most commonly used vectors in the manufacturing process. However, the integration pattern of these viral vectors and subsequent effect on CAR T-cell products is still unclear. Methods We used a modified viral integration sites analysis (VISA) pipeline to evaluate viral integration events around the whole genome in pre-infusion CAR T-cell products. We compared the differences of integration pattern between lentiviral and γ-retroviral products. We also explored whether the integration sites correlated with clinical outcomes. Results We found that γ-retroviral vectors were more likely to insert than lentiviral vectors into promoter, untranslated, and exon regions, while lentiviral vector integration sites were more likely to occur in intron and intergenic regions. Some integration events affected gene expression at the transcriptional and post-transcriptional level. Moreover, γ-retroviral vectors showed a stronger impact on the host transcriptome. Analysis of individuals with different clinical outcomes revealed genes with differential enrichment of integration events. These genes may affect biological functions by interrupting amino acid sequences and generating abnormal proteins, instead of by affecting mRNA expression. These results suggest that vector integration is associated with CAR T-cell efficacy and clinical responses. Conclusion We found differences in integration patterns, insertion hotspots and effects on gene expression vary between lentiviral and γ-retroviral vectors used in CAR T-cell products and established a foundation upon which we can conduct further analyses.

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“…Recently, increasing researches reported that neutrophils, an important component of the microenvironment, play crucial roles in tumor innate immunity in ovarian cancer (28). Tiffany et al found that complementdependent priming of neutrophil functions induced a T-cell immunoparalysis, which was identi ed as targets for immunotherapy (22). But the mechanisms for regulating neutrophil, especially the phenotypic and functional heterogeneity of neutrophils in tumors were rarely reported.…”

Section: Discussionmentioning

confidence: 99%

“…Although TANs were reported to be associated with the development and prognosis of various malignant tumors, including kidney cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, malignant melanoma and so on (13)(14)(15)(16)(17)(18), and researches about the different relationships, such as the neutrophil-tolymphocyte ratio(NLR), treatment effects and prognosis, between neutrophils and ovarian cancer were also reported recently (19)(20)(21)(22), the roles and mechanisms of neutrophils in invasion and metastasis of ovarian cancer still remains unknown. This research intends to verify the roles and mechanisms of different neutrophils phenotypes in invasion and metastasis of ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

N2-neutrophils promote invasion and metastasis of ovarian cancer by upregulating MAPK signaling

Zhou

Men

et al. 2022

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Background Neutrophils is an important immune cell in microenvironment of various cancers. Previous studies reported that neutrophils were associated with the development and prognosis of various malignant tumors, but how different phenotypic and functional heterogeneity of neutrophils exert in regulating invasion and metastasis of ovarian cancer were rare reported. Objective This study aimed to verify functions and mechanisms of different phenotypes of neutrophils in ovarian cancer invasion and metastasis. Methods The expression of CD11b, one of the most important biomarkers of N2-neutrophils, was assessed by immunohistochemistry and western blot (WB) in 24 benign and malignant clinical ovarian cancer tissues respectively. 48 samples from 16 ovarian serous carcinoma patients were averagely divide into adjacent tissues, primary lesions and metastatic lesions groups, detecting the mRNA and protein expression levels of neutrophil biomarkers CD11b, CXCL8 and CXCR1 by reverse-transcription quantitative PCR (qRT–PCR) and WB. Tumor associated N1 and N2 neutrophils phenotypes research models were constructed. Invasion and metastasis changes of ovarian cancer cells were assessed by transwell assay and wound-healing test with or without N1/N2 neutrophils co-culturing. The roles and mechanisms of N2-neutrophils in promoting ovarian cancer progression were probed by high-throughput RNA sequencing and gain- and loss-of-function analysis. Results The expression of CD11b was significantly increased in malignant tissue groups compared with benign groups. The expression levels of CD11b, CXCL8 and CXCR1 were the highest in groups of metastatic lesions, followed by the primary lesions, and the lowest in the adjacent tissues. N2-neutrophils co-cultured with ovarian cancer cell lines (SKOV3 and OVCAR3) could promote the invasion and metastasis of ovarian cancer cell lines, but N1-neutrophils played the opposite role. MAPK signaling pathway was significantly enhanced in ovarian cancer cells by phosphorylating of P38 after co-culturing with N2-neutrophils and the p-P38 mono-inhibitor was able to reverse this function. Conclusions N2-neutrophils promoted the invasion and metastasis of ovarian cancer by upregulating MAPK signaling through phosphorylating the P38.

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Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer

Cited by 28 publications

References 66 publications

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products

N2-neutrophils promote invasion and metastasis of ovarian cancer by upregulating MAPK signaling

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