Novel Lymphocyte-Independent Antitumor Activity by PD-1 Blocking Antibody against PD-1+ Chemoresistant Lung Cancer Cells

Autor: Ramona Rotolo, Valeria Leuci, Chiara Donini, Federica Galvagno, Annamaria Massa, Maria Chiara De Santis, Serena Peirone, Giovanni Medico, Martina Sanlorenzo, Igor Vujic, Loretta Gammaitoni, Marco Basiricò, Luisella Righi, Chiara Riganti, Iris Chiara Salaroglio, Francesca Napoli, Fabrizio Tabbò, Annapaola Mariniello, Elisa Vigna, Chiara Modica, Lorenzo D’Ambrosio, Giovanni Grignani, Riccardo Taulli, Emilio Hirsch, Matteo Cereda, Massimo Aglietta, Giorgio Vittorio Scagliotti, Silvia Novello, Paolo Bironzo, Dario Sangiolo
Přispěvatelé: Rotolo, Ramona, Leuci, Valeria, Donini, Chiara, Galvagno, Federica, Massa, Annamaria, De Santis, Maria Chiara, Peirone, Serena, Medico, Giovanni, Sanlorenzo, Martina, Vujic, Igor, Gammaitoni, Loretta, Basiricò, Marco, Righi, Luisella, Riganti, Chiara, Salaroglio, Iris Chiara, Napoli, Francesca, Tabbò, Fabrizio, Mariniello, Annapaola, Vigna, Elisa, Modica, Chiara, D'Ambrosio, Lorenzo, Grignani, Giovanni, Taulli, Riccardo, Hirsch, Emilio, Cereda, Matteo, Aglietta, Massimo, Scagliotti, Giorgio Vittorio., Novello, Silvia, Bironzo, Paolo, Sangiolo, Dario
Rok vydání: 2022
Předmět:
Zdroj: Clinical Cancer Research. 29:621-634
ISSN: 1557-3265
1078-0432
DOI: 10.1158/1078-0432.ccr-22-0761
Popis: Purpose: Antibodies against the lymphocyte PD-1 (aPD-1) receptor are cornerstone agents for advanced non–small cell lung cancer (NSCLC), based on their ability to restore the exhausted antitumor immune response. Our study reports a novel, lymphocyte-independent, therapeutic activity of aPD-1 against NSCLC, blocking the tumor-intrinsic PD-1 receptors on chemoresistant cells. Experimental Design: PD-1 in NSCLC cells was explored in vitro at baseline, including stem-like pneumospheres, and following treatment with cisplatin both at transcriptional and protein levels. PD-1 signaling and RNA sequencing were assessed. The lymphocyte-independent antitumor activity of aPD-1 was explored in vitro, by PD-1 blockade and stimulation with soluble ligand (PD-L1s), and in vivo within NSCLC xenograft models. Results: We showed the existence of PD-1+ NSCLC cell subsets in cell lines and large in silico datasets (Cancer Cell Line Encyclopedia and The Cancer Genome Atlas). Cisplatin significantly increased PD-1 expression on chemo-surviving NSCLC cells (2.5-fold P = 0.0014), while the sequential treatment with anti–PD-1 Ab impaired their recovery after chemotherapy. PD-1 was found to be associated with tumor stemness features. PD-1 expression was enhanced in NSCLC stem-like pneumospheres (P < 0.0001), significantly promoted by stimulation with soluble PD-L1 (+27% ± 4, P < 0.0001) and inhibited by PD-1 blockade (−30% ± 3, P < 0.0001). The intravenous monotherapy with anti–PD-1 significantly inhibited tumor growth of NSCLC xenografts in immunodeficient mice, without the contribution of the immune system, and delayed the occurrence of chemoresistance when combined with cisplatin. Conclusions: We report first evidence of a novel lymphocyte-independent activity of anti–PD-1 antibodies in NSCLC, capable of inhibiting chemo-surviving NSCLC cells and exploitable to contrast disease relapses following chemotherapy. See related commentary by Augustin et al., p. 505
Databáze: OpenAIRE
Externí odkaz: