TY - JOUR
T1 - Reduction of T Lymphoma Cells and Immunological Invigoration in a Patient Concurrently Affected by Melanoma and Sezary Syndrome Treated With Nivolumab
AU - Narducci, Maria Grazia
AU - Tosi, Anna
AU - Frezzolini, Alessandra
AU - Scala, Enrico
AU - Passarelli, Francesca
AU - Bonmassar, Laura
AU - Monopoli, Alessandro
AU - Accetturi, Maria Pina
AU - Cantonetti, Maria
AU - Antonini Cappellini, Gian Carlo
AU - De Galitiis, Federica
AU - Rosato, Antonio
AU - Picozza, Mario
AU - Russo, Giandomenico
AU - D’Atri, Stefania
N1 - Funding Information: We sincerely thank the patient who contributed to this study. We would also like to thank Prof. Ornella Franzese (Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy) for valuable discussion, Dr. Marie Perez (Histopathology Unit, IDI-IRCCS) for TCR-V? analysis performed in skin lesion biopsies, and Dr. Antonella Bresin (Laboratory of Molecular Oncology, IDI-IRCCS, Rome, Italy) for her assistance for figures preparation. Funding. This study was supported by the AIRC (IG 17048_2015 to MN), Italian Ministry of Health (Grant PE-2016-02364102 to GR), and Associazione Volontari per il Policlinico Tor Vergata, ONLUS. Publisher Copyright: © Copyright © 2020 Narducci, Tosi, Frezzolini, Scala, Passarelli, Bonmassar, Monopoli, Accetturi, Cantonetti, Antonini Cappellini, De Galitiis, Rosato, Picozza, Russo and D’Atri. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
M1 - 579894
PY - 2020/9/25
Y1 - 2020/9/25
N2 - Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients’ response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients’ response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).
AB - Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients’ response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients’ response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (ClinicalTrials.gov NCT03385226, NCT04118868).
KW - cutaneous T-cell lymphoma
KW - granzyme B
KW - immune sub-populations
KW - Ki67 proliferation index
KW - PD-1 blockade therapy
U2 - 10.3389/fimmu.2020.579894
DO - 10.3389/fimmu.2020.579894
M3 - Article
VL - 11
JO - Front. Immunol.
JF - Front. Immunol.
SN - 1664-3224
ER -