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Author Notes:

Domenico Galati, Email: d.galati@istitutomori.na.it

Study conception and design: DG, PAA; collection and interpretation of data: DG, SZ, MC, GM; statistical analysis: DG, SZ, MC; manuscript drafting: DG, CMP, PAA; manuscript editing: DG, SZ, MC, CMP, PAA; approval to submit: DG, SZ, MC, MG, DM, MR, ES, LF, FS, RA, RDF, AP, CMP, PAA. All authors read and approved the final manuscript.

PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, and Sanofi. Travel support by Pfizer, Bio-Al Health, and Replimmune. AP declares lectures honoraria from Hoffmann-La Roche AG, Incyte–Italy, Merck Sharp and Dohme, Bristol-Meyers Squibb, and participation to scientific advisory boards for F. Hoffmann-La Roche AG, Merck Sharp, and Dohme, Takeda, and Incyte-Italy. All other authors have declared no conflicts of interest.


Research Funding:

This work was supported by Grants from the Italian Ministry of Health (IT-MOH) through “Ricerca Corrente”.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • Melanoma
  • Nivolumab
  • PD1-Ab
  • Immunotherapy
  • CD26
  • Flow cytometry
  • Cancer biomarkers

Potential clinical implications of CD4(+)CD26(high) T cells for nivolumab treated melanoma patients

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Journal Title:



Volume 21, Number 1


, Pages 318-318

Type of Work:

Article | Final Publisher PDF


Background: Nivolumab is an anti-PD1 antibody that has dramatically improved metastatic melanoma patients’ outcomes. Nevertheless, many patients are resistant to PD-1 inhibition, occasionally experiencing severe off-target immune toxicity. In addition, no robust and reproducible biomarkers have yet been validated to identify the correct selection of patients who will benefit from anti-PD-1 treatment avoiding unwanted side effects. However, the strength of CD26 expression on CD4+ T lymphocytes permits the characterization of three subtypes with variable degrees of responsiveness to tumors, suggesting that the presence of CD26-expressing T cells in patients might be a marker of responsiveness to PD-1-based therapies. Methods: The frequency distribution of peripheral blood CD26-expressing cells was investigated employing multi-parametric flow cytometry in 69 metastatic melanoma patients along with clinical characteristics and blood count parameters at baseline (W0) and compared to 20 age- and sex-matched healthy controls. Percentages of baseline CD4+CD26high T cells were correlated with the outcome after nivolumab treatment. In addition, the frequency of CD4+CD26high T cells at W0 was compared with those obtained after 12 weeks (W1) of therapy in a sub-cohort of 33 patients. Results: Circulating CD4+CD26high T cells were significantly reduced in melanoma patients compared to healthy subjects (p = 0.001). In addition, a significant association was observed between a low baseline percentage of CD4+CD26high T cells (< 7.3%) and clinical outcomes, measured as overall survival (p = 0.010) and progression-free survival (p = 0.014). Moreover, patients with clinical benefit from nivolumab therapy had significantly higher frequencies of circulating CD4+CD26high T cells than patients with non-clinical benefit (p = 0.004) at 12 months. Also, a higher pre-treatment proportion of circulating CD4+CD26high T cells was correlated with Disease Control Rate (p = 0.014) and best Overall Response Rate (p = 0.009) at 12 months. Interestingly, after 12 weeks (W1) of nivolumab treatment, percentages of CD4+CD26high T cells were significantly higher in comparison with the frequencies measured at W0 (p < 0.0001), aligning the cell counts with the ranges seen in the blood of healthy subjects. Conclusions: Our study firstly demonstrates that peripheral blood circulating CD4+CD26high T lymphocytes represent potential biomarkers whose perturbations are associated with reduced survival and worse clinical outcomes in melanoma patients.

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© The Author(s) 2023

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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