IL-6–targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function

Speake, Cate; Habib, Tania; Lambert, Katharina; Hundhausen, Christian; Lord, Sandra; Dufort, Matthew J.; Skinner, Samuel O.; Hu, Alex; Kinsman, MacKenzie; Jones, Britta E.; Maerz, Megan D.; Tatum, Megan; Hocking, Anne M.; Nepom, Gerald T.; Greenbaum, Carla J.; Buckner, Jane H.

doi:10.1172/jci.insight.159436

Cited by 6 publications

(5 citation statements)

References 48 publications

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“…Although inhibition of IL-6 or IL-6R was considered to result in comparable signalling outcomes, a recent publication using a single side-by-side administration protocol for siltuximab and tocilizumab in patients with type 1 diabetes reported differences between the two antibodies 89 . The authors describe distinct influences on T cell function, because siltuximab but not tocilizumab enhanced the suppression of effector T cells by regulatory T cells 89 . As this is the first in vivo study addressing this issue, it might simply be related to differences in dosing and pharmacokinetics 89 .…”

Section: Development Of Il-6 Signalling Inhibitorsmentioning

confidence: 99%

“…The authors describe distinct influences on T cell function, because siltuximab but not tocilizumab enhanced the suppression of effector T cells by regulatory T cells 89 . As this is the first in vivo study addressing this issue, it might simply be related to differences in dosing and pharmacokinetics 89 . However, it might also, at least in part, be caused by IL-6 family cytokine crosstalk.…”

Section: Development Of Il-6 Signalling Inhibitorsmentioning

confidence: 99%

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Targeting IL-6 trans-signalling: past, present and future prospects

et al. 2023

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Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed ‘mIL-6R’) and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling — known as cluster signalling — involves preformed complexes of membrane-bound IL-6–mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.

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Section: Development Of Il-6 Signalling Inhibitorsmentioning

confidence: 99%

Section: Development Of Il-6 Signalling Inhibitorsmentioning

confidence: 99%

Targeting IL-6 trans-signalling: past, present and future prospects

et al. 2023

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“…The 24-hour IC 50s of resistant cells were first tested by CCK8 assay. The results showed the IC 50 values of anlotinib monotherapy for KHOS-R and 143B-R were 23.76μM and 16.91μM, combined with 100ng/ml tocilizumab (an IL-6R inhibitor) ( 29 ), the IC 50s were reverted to 12.70μM and 9.388μM respectively ( Figure 3A ). The cell proliferation viability results indicated that 100ng/ml tocilizumab affected proliferation of resistant cells lightly, but combination with anlotinib obviously diminished proliferation viability and regained sensitivity to anlotinib according to colony formation and EDU assays ( Figures 3B–E ).…”

Section: Resultsmentioning

confidence: 99%

Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma

Chen

Sun

et al. 2023

Front. Oncol.

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PurposeAnlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS.Materials and MethodsIn this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC.ResultsWe found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis.ConclusionTocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS.

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“…In the patients treated with Siltuximab, IL-6 and other PCy levels increased post-HDC/ASCT. There is evidence that an IL-6 blockade may result in a paradoxical increase in IL-6 and systemic inflammation [ 49 , 50 ]; however, there were no significant associations with the neurocognitive and neuroimaging outcomes. Additional research would be required to reconcile our preliminary findings with the role of MM and its treatment on PCy dysregulation and treatment-related neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Neuroimaging and Neurocognitive Outcomes in Older Patients with Multiple Myeloma Treated with Chemotherapy and Autologous Stem Cell Transplantation

Correa,

Vachha,

Baser

et al. 2023

Cancers

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There is a paucity of research on treatment-related neurotoxicity in older adults with multiple myeloma (MM) treated with high-dose chemotherapy (HDC) and autologous SCT (HDC/ASCT), despite the increasing use of this regimen. We examined resting state functional connectivity (RSFC), gray matter (GM) volume, neurocognitive function (NF), and proinflammatory cytokines (PCy) in older patients with MM pre- and post-HDC/ASCT. Eighteen patients underwent MRI, NF tests, and serum PCy measurements prior to HDC/ASCT, and fifteen patients completed a follow up five-months post-HDC/ASCT. There were significant decreases in RSFC post-HDC/ASCT in (1) the central executive network (CEN) involving the left dorsolateral prefrontal cortex and right posterior parietal cortex (p = 0.022) and (2) the CEN involving the right posterior parietal cortex and the salience network involving the right dorsal anterior cingulate cortex (p = 0.029). There were no significant changes in GM or NF, except for improvements in attention (Digit Span Backward, p = 0.03). There were significant increases in several PCy post-HDC/ASCT (p ≤ 0.05). In conclusion, RSFC decreased in frontal, parietal, and cingulate cortices post-HDC/ASCT, NF was relatively stable, and several PCy increased. These findings are congruent with other studies in cancer patients and provide supporting evidence for the vulnerability of frontoparietal regions to chemotherapy’s adverse effects.

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IL-6–targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function

Cited by 6 publications

References 48 publications

Targeting IL-6 trans-signalling: past, present and future prospects

Targeting IL-6 trans-signalling: past, present and future prospects

Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma

Neuroimaging and Neurocognitive Outcomes in Older Patients with Multiple Myeloma Treated with Chemotherapy and Autologous Stem Cell Transplantation

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