Using SILAC-based mass spectrometry, Grimaldi and Cammarata et al. identified several upregulated, fragmented native proteins as non-mutated NeoAgs generated by chemotherapy-induced apoptosis and caspase-dependent proteolytic activity in NSCLC cells. T effector cells (CD8+ and CD4+) obtained from NSCLC patients treated with cisplatin or cisplatin and nivolumab recognized the non-mutated NeoAgs (INFγ and/or TNFα production) when pulsed with non-mutated NeoAgs peptides. T effector cell response was highest in the combination therapy and correlated with patient survival and decreased PD-1 expression.
Contributed by Shishir Pant
ABSTRACT: Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4(+) and CD8(+) T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients' survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients.
Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Univ
Author Info: (1) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (2) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (3) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (4) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (5) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (6) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. (7) Dipartimento di Medicina Molecolare, Sapienza Universita di Roma, 00161, Rome, Italy. (8) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (9) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (10) Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. (11) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (12) Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy. IRCCS Neuromed, Pozzilli, Isernia, Italy. (13) Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Universita di Roma - Polo Pontino, 04100, Latina, Italy. (14) Dipartimento di Scienze e Biotecnologie Medico-Chirurgiche, Sapienza Universita di Roma - Polo Pontino, 04100, Latina, Italy. (15) UOC Oncologia Universitaria, ASL Latina (distretto Aprilia), Sapienza Universita di Roma, Via Giustiniano snc, 04011, Aprilia, Latina, Italy. (16) Dipartimento di Medicina Molecolare, Sapienza Universita di Roma, 00161, Rome, Italy. (17) Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. (18) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (19) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (20) Tumor Immunology and Immunotherapy Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (21) Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (22) Unit of Pathology, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (23) Thoracic Surgery Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy. (24) Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Oncologia Medica, Universita di Roma, 00161, Rome, Italy. (25) Dipartimento di Medicina Interna e Specialita Mediche, Sapienza Universita di Roma, 00161, Rome, Italy. vincenzo.barnaba@uniroma1.it. Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. vincenzo.barnaba@uniroma1.it. Istituto Pasteur - Fondazione Cenci Bolognetti, 00185, Rome, Italy. vincenzo.barnaba@uniroma1.it.
