TY - JOUR
T1 - Altered Frequencies and Functions of Innate Lymphoid Cells in Melanoma Patients Are Modulated by Immune Checkpoints Inhibitors
AU - Cristiani, Costanza Maria
AU - Capone, Mariaelena
AU - Garofalo, Cinzia
AU - Madonna, Gabriele
AU - Mallardo, Domenico
AU - Tuffanelli, Marilena
AU - Vanella, Vito
AU - Greco, Marta
AU - Foti, Daniela Patrizia
AU - Viglietto, Giuseppe
AU - Ascierto, Paolo Antonio
AU - Spits, Hergen
AU - Carbone, Ennio
N1 - Funding Information: This work was supported by Italian Association for Cancer Research (IG15521 and IG20312); Wenner-Gren Foundation, Sweden; Fondazione Melanoma Onlus, Naples; Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) PRIN 2017 2017M8YMR8_002; Fondazione NIBIT, Siena, Italy (grants to EC) and Italian Ministry of Health (IT-MOH) through “Ricerca Corrente”, grants number M2-2 (grants to PAA). CMC was supported by EFIS-IL Short Term Fellowship and EACR Travel Fellowship. Funding Information: Conflict of Interest: PA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Array, Merck Serono, Pierre-Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Takis, Lunaphore. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Array, Sanofi and travel support from MSD. HS has a consultant role for SGK. All outside the submitted work. Publisher Copyright: Copyright © 2022 Cristiani, Capone, Garofalo, Madonna, Mallardo, Tuffanelli, Vanella, Greco, Foti, Viglietto, Ascierto, Spits and Carbone.
PY - 2022/1/31
Y1 - 2022/1/31
N2 - Monoclonal antibodies targeting immune checkpoints improved clinical outcome of patients with malignant melanoma. However, the mechanisms are not fully elucidated. Since immune check-point receptors are also expressed by helper innate lymphoid cells (ILCs), we investigated the capability of immune checkpoints inhibitors to modulate ILCs in metastatic melanoma patients as well as melanoma cells effects on ILC functions. Here, we demonstrated that, compared to healthy donors, patients showed a higher frequency of total peripheral ILCs, lower percentages of CD117+ ILC2s and CD117+ ILCs as well as higher frequencies of CD117- ILCs. Functionally, melanoma patients also displayed an impaired TNFα secretion by CD117- ILCs and CD117+ ILCs. Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117- ILC2s and enhanced the capability of ILC2s and CD117+ ILCs to secrete IL-13 and TNFα, respectively. Before Nivolumab therapy, high CCL2 serum levels were associated with longer Overall Survival and Progression Free Survival. After two months of treatment, CD117- ILC2s frequency as well as serum concentrations of IL-6, CXCL8 and VEGF negatively correlated with both the parameters. Moreover, melanoma cells boosted TNFα production in all ILC subsets and increased the number of IL-13 producing ILC2s in vitro. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response.
AB - Monoclonal antibodies targeting immune checkpoints improved clinical outcome of patients with malignant melanoma. However, the mechanisms are not fully elucidated. Since immune check-point receptors are also expressed by helper innate lymphoid cells (ILCs), we investigated the capability of immune checkpoints inhibitors to modulate ILCs in metastatic melanoma patients as well as melanoma cells effects on ILC functions. Here, we demonstrated that, compared to healthy donors, patients showed a higher frequency of total peripheral ILCs, lower percentages of CD117+ ILC2s and CD117+ ILCs as well as higher frequencies of CD117- ILCs. Functionally, melanoma patients also displayed an impaired TNFα secretion by CD117- ILCs and CD117+ ILCs. Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117- ILC2s and enhanced the capability of ILC2s and CD117+ ILCs to secrete IL-13 and TNFα, respectively. Before Nivolumab therapy, high CCL2 serum levels were associated with longer Overall Survival and Progression Free Survival. After two months of treatment, CD117- ILC2s frequency as well as serum concentrations of IL-6, CXCL8 and VEGF negatively correlated with both the parameters. Moreover, melanoma cells boosted TNFα production in all ILC subsets and increased the number of IL-13 producing ILC2s in vitro. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response.
KW - cytokines
KW - immune checkpoints inhibitors
KW - innate lymphoid cells
KW - melanoma
KW - nivolumab
UR - http://www.scopus.com/inward/record.url?scp=85124621396&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2022.811131
DO - https://doi.org/10.3389/fimmu.2022.811131
M3 - Article
C2 - 35173725
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 811131
ER -