Potential clinical implications of CD4+CD26high T cells for nivolumab treated melanoma patients.

Abstract

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.

• Authors: Domenico Galati, Serena Zanotta, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Marilena Romanelli, Ester Simeone, Lucia Festino, Francesca Sparano, Rosa Azzaro, Rosaria De Filippi, Antonio Pinto, Chrystal M Paulos, Paolo A Ascierto
• Journal: Journal of translational medicine (J Transl Med) Vol. 21 Issue 1 Pg. 318 (05 11 2023) ISSN: 1479-5876 [Electronic] England
• PMID: 37170241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023. The Author(s).

Chemical References

• Nivolumab
• Dipeptidyl Peptidase 4

Topics

• Humans
• Nivolumab (pharmacology, therapeutic use)
• T-Lymphocytes
• Dipeptidyl Peptidase 4 (therapeutic use)
• Melanoma (pathology)
• Progression-Free Survival