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| Item Type: | Article |
|---|---|
| Title: | Reduced monocytic IL10 expression in PD1 inhibitor-treated patients is a harbinger of severe immune-related adverse events |
| Creators: |
Rosnev, S.  ORCID: https://orcid.org/0000-0003-0256-7038, Sterner, B. ORCID: https://orcid.org/0000-0001-8882-3885, Schiele, P. ORCID: https://orcid.org/0000-0002-2342-3597, Kolling, S., Martin, M. ORCID: https://orcid.org/0000-0001-9549-6843, Flörcken, A., Erber, B., Wittenbecher, F., Kofla, G., Kurreck, A., Lang, T.J.L. ORCID: https://orcid.org/0000-0003-0566-196X, von Einem, J.C. ORCID: https://orcid.org/0000-0001-8843-9541, de Santis, M., Pelzer, U. ORCID: https://orcid.org/0000-0001-9213-2737, Stintzing, S. ORCID: https://orcid.org/0000-0002-3297-5801, Bullinger, L. ORCID: https://orcid.org/0000-0002-5890-5510, Klinghammer, K. ORCID: https://orcid.org/0000-0001-6425-4833, Geisel, D. ORCID: https://orcid.org/0000-0001-7348-0971, Ochsenreither, S., Frentsch, M. and Na, I.K. ORCID: https://orcid.org/0000-0001-9902-5424
|
| Abstract: | BACKGROUND: Despite remarkable clinical efficacy, little is known about the system-wide immunological alterations provoked by PD1 blockade. Dynamics of quantitative immune composition and functional repertoire during PD1 blockade could delineate cohort-specific patterns of treatment response and therapy-induced toxicity. METHODS: We longitudinally assessed therapy-induced effects on the immune system in fresh whole blood using flow cytometry-based cell quantifications, accompanied by analyses of effector properties of all major immune populations upon cell-type specific stimulations. 43 cancer patients undergoing PD1 blockade were recruited with assessments performed pre-treatment and before cycles 2/4/6, which resulted in the collection of more than 30,000 cytometric data values. RESULTS: We observed no intrinsic immune pattern correlating with clinical outcome before PD1 blockade initiation, but cohort-specific immune alterations emerged during therapy. The most striking evolving changes in therapy responders were an increase in activated T and NK cell subsets, which showed high IFNγ and TNFα expression upon ex vivo stimulation. Patients affected by severe immune-related adverse events (s-irAE) presented with an analogously increased number of activated CD4(+) and CD8(+) T cells compared to patients with no/mild irAE, but lacked the functional divergences observed between responders versus non-responders. Instead, their monocytes showed discriminatory functional deficits with less IL10 production upon stimulation, which led to an abrogated inhibition of T cell proliferation in vitro and thus may account for the observed T cell expansion in patients with s-irAE. CONCLUSION: Our holistic explorative approach allowed the delineation of clinically relevant cohorts by treatment-triggered immune changes, potentially enabling better patient stratification and further revealed new mechanistic insights into the pathogenesis of s-irAE. |
| Keywords: | Cancer Immunotherapy, Immune Checkpoint Blockade, PD1, Immune-Related Adverse Events, Biomarkers, Monocytes, IL10 |
| Source: | European Journal of Cancer |
| ISSN: | 0959-8049 |
| Publisher: | Elsevier |
| Volume: | 217 |
| Page Range: | 115252 |
| Date: | 25 February 2025 |
| Official Publication: | https://doi.org/10.1016/j.ejca.2025.115252 |
| PubMed: | View item in PubMed |
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