CD8<sup>+</sup>T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain

Krukowski, Karen; Eijkelkamp, Niels; Laumet, Geoffroy; Hack, C. E.; Li, Yan; Dougherty, Patrick M.; Heijnen, Cobi J.; Kavelaars, Annemieke

doi:10.1523/jneurosci.3708-15.2016

Cited by 172 publications

(203 citation statements)

References 65 publications

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“…107 Conversely, intrathecal IL-10 gene therapy or the intrathecal administration of recombinant IL-10 has been shown to progressively reverse the allodynic state associated with paclitaxel treatment. 96,108 In vitro, IL-10 suppressed paclitaxel-induced spontaneous discharges in DRG neurons. 108 It is interesting to note that we recently found that spontaneous resolution of CIPN depends on endogenous IL-10 signaling; blocking IL-10 signaling through the intrathecal administration of a neutralizing antibody delayed recovery from CIPN.…”

Section: Contribution Of Nitro-oxidative Stress To Cipnmentioning

confidence: 99%

“…With respect to regulatory cytokines, oxaliplatin‐induced mechanohypersensitivity is associated with reduced levels of the anti‐inflammatory cytokines IL‐10 and IL‐4 in the spinal dorsal horn . Conversely, intrathecal IL‐10 gene therapy or the intrathecal administration of recombinant IL‐10 has been shown to progressively reverse the allodynic state associated with paclitaxel treatment . In vitro, IL‐10 suppressed paclitaxel‐induced spontaneous discharges in DRG neurons …”

Section: Introductionmentioning

confidence: 99%

“…Conversely, intrathecal IL‐10 gene therapy or the intrathecal administration of recombinant IL‐10 has been shown to progressively reverse the allodynic state associated with paclitaxel treatment . In vitro, IL‐10 suppressed paclitaxel‐induced spontaneous discharges in DRG neurons …”

Section: Introductionmentioning

confidence: 99%

“…Fingolimod, A 3 AR agonists, and minocycline are candidates for targeting the proinflammatory pathways that contribute to CIPN . IL‐10 gene therapy or recombinant IL‐10 treatment may represent a more efficacious approach to promote recovery from CIPN in both patients with cancer and cancer survivors because it engages natural pain resolution pathways and therefore is likely to have true disease‐modifying effects …”

Section: Introductionmentioning

confidence: 99%

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Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Kavelaars

Dougherty

et al. 2018

Cancer

126

111

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Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is important to note that such interventions should not interfere with the antitumor effects of chemotherapy. Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy "currency" adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Herein, the authors discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system. Cancer 2018;124:2289-98. © 2018 American Cancer Society.

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Section: Contribution Of Nitro-oxidative Stress To Cipnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Kavelaars

Dougherty

et al. 2018

Cancer

126

111

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“…For example, IL4 and IL12-induced IL10-expressing CD8 T cells was shown to inhibit graft-versus-host disease in vivo, and suppressed naive and effector T cell activation and IgG/IgE production [32]. Interestingly, CD8 T cell-mediated IL10 was shown to resolve chemotherapy-induced neuropathic pain [33]. Hence, IL10 expression might serve multiple roles in CD8 T cells, and the function of IFNg/IL10-double positive CD8 T cells should be further investigated using animal models.…”

Section: Discussionmentioning

confidence: 99%

Gastric cancer patients display a distinctive population of IFNg+IL10+ double positive CD8 T cells, which persists longer during prolonged activation

Chen¹,

Song

Li³

2019

Experimental Cell Research

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IL10 is generally regarded as a broad-spectrum regulatory cytokine. However, the role of IL10 in CD8 T cells remains controversial. In this study, we investigated the characteristics of endogenous IL10 by CD8 T cells in gastric cancer (GC) patients. Using intracellular staining, we found that in both GC patients and healthy controls, the majority of IL10-expressing CD8 T cells also presented concurrent IFNg expression. Interestingly, the frequency of IFNg + IL10 + CD8 T cells was significantly higher in GC patients than in healthy controls, while the frequency of IFNg + IL10 -CD8 T cells was significantly lower in GC patients than in healthy controls. Compared to the IFNg -IL10 -CD8 T cells, both IFNg + IL10and IFNg + IL10 + CD8 T cells presented significantly higher expression of activation/inhibitory markers. Interestingly, the IFNg + IL10 + cells presented lower PD1 and TIM3 and higher KLRG1 than the IFNg + IL10 -CD8 T cells. Remarkably, the IFNg + IL10 + CD8 T cells, but not the IFNg + IL10 -CD8 T cells, were highly enriched in the CD45RO + CXCR5 + subset. Prolonged activation resulted in significant enrichment of IFNg + IL10 + CD8 T cells over time. Interestingly, compared to the CD45RO + CXCR5 -CD8 T cells, the CD45RO + CXCR5 + CD8 T cells presented stronger proliferation capacity at later stages of stimulation, and higher viability throughout the stimulation process. Overall, our investigation demonstrated that GC patients were enriched with a distinctive population of IFNg + IL10 + double positive CD8 T cells, which resembled T follicular cytotoxic cells and could persist longer during prolonged activation.

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Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

Germain

O’Mara

Robinson

et al. 2020

Cancer

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BACKGROUND: To the authors' knowledge, the empiric identification of agents and interventions to mitigate chemotherapy-induced peripheral neuropathy (CIPN) has resulted in only 1 agent that modestly mitigates it and no agents or interventions that prevent its development. This speaks to the need for a mechanistic understanding of CIPN to develop effective interventions. METHODS: To understand the extent to which mechanistic understanding of CIPN is being translated into the development of interventions, the National Cancer Institute conducted a review of the National Institutes of Health (NIH)'s portfolio of investigator-initiated grants, the literature regarding CIPN mechanisms, and the clinical trials listed in the ClinicalTrials.gov database from January 1, 2011, to May 22, 2019. RESULTS: A total of 69 NIH-supported grants and 95 published articles were identified that evaluated mechanistic pathways of 7 different chemotherapy agents that cause CIPN. The review also identified 35 clinical trials that investigated agents or devices with which to treat CIPN. Only 3 trials incorporated a mechanistic rationale to support the choice of the intervention. CONCLUSIONS: To the authors' knowledge, very little of the mechanistic understanding of the development of CIPN is being translated into intervention rationale in clinical trials that evaluate interventions to mitigate CIPN. Efforts to incentivize this translation are needed. Cancer 2020;126:4602-4613.

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CD8⁺T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain

Cited by 172 publications

References 65 publications

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Gastric cancer patients display a distinctive population of IFNg+IL10+ double positive CD8 T cells, which persists longer during prolonged activation

Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

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CD8+T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain

Cited by 172 publications

References 65 publications

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Beyond symptomatic relief for chemotherapy‐induced peripheral neuropathy: Targeting the source

Gastric cancer patients display a distinctive population of IFNg+IL10+ double positive CD8 T cells, which persists longer during prolonged activation

Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design

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CD8⁺T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain