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

• Authors: Domenico Galati, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Serena Zanotta, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Mariaelena Capone, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Gabriele Madonna, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Domenico Mallardo, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Marilena Romanelli, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Ester Simeone, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Lucia Festino, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Francesca Sparano, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Rosa Azzaro, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Rosaria De Filippi, Univ Federico II; Antonio Pinto, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy; Chrystal Paulos, Emory University; Paolo A Ascierto, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Italy
• Journal Title: JOURNAL OF TRANSLATIONAL MEDICINE
• Volume: Volume 21, Number 1
• Publisher: BMC | 2023-05-11, Pages 318-318
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1186/s12967-023-04184-6
• Subjects: Health Sciences, Immunology; Biology, Microbiology; Health Sciences, Oncology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; Melanoma; Nivolumab; PD1-Ab; Immunotherapy; CD26; Flow cytometry; Cancer biomarkers; METASTATIC MELANOMA; ADENOSINE-DEAMINASE; CD26 EXPRESSION; SURVIVAL; PERSISTENCE; IPILIMUMAB; GUIDELINES

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.