Naigeon et al. identified cytomegalovirus (CMV), among human-tropic viruses, as the major (necessary but not sufficient) viral driver of T cell senescence in patients with advanced NSCLC. Senescent CD8+ T (T8sen) cells showed higher expression of the T-bet and β-galactosidase, and lower proliferation and IL2 expression compared to other CD8+ T cell populations. T8senhigh status is not associated with a polyclonal antibody response against CMV but is observed in patients whose T cells recognize an MHC II–restricted CMV epitope. The proportion of T8sen cells increased with cancer progression in CMV+ patients and is associated with poor outcome in aNSCLC patients treated with anti–PD-L1 therapy.
Contributed by Shishir Pant
ABSTRACT: Circulating senescent CD8(+) T (T(8)sen) cells are characterized by a lack of proliferative capacities but retain cytotoxic activity and have been associated to resistance to immunotherapy in patients with advanced non-small cell lung cancer (aNSCLC). We aimed to better characterize T(8)sen and to determine which factors were associated with their accumulation in patients with aNSCLC. Circulating T(8)sen cells were characterized by a higher expression of SA-_gal and the transcription factor T-bet, confirming their senescent status. Using whole virome profiling, cytomegalovirus (CMV) was the only virus associated with T(8)sen. CMV was necessary but not sufficient to explain high accumulation of T(8)sen (T(8)sen(high) status). In CMV(+) patients, the proportion of T(8)sen cells increased with cancer progression. Last, CMV-induced T(8)sen(high) phenotype but not CMV seropositivity itself was associated with worse progression-free and overall survival in patients treated with anti-PD-(L)1 therapy but not with chemotherapy. Overall, CMV is the unique viral driver of T(8)sen-driven resistance to anti-PD-(L)1 antibodies in patients with aNSCLC.
Author Info: (1) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Facult de Mdecine, Universit Paris-Saclay, Le Kremlin-Bictre, Fr
Author Info: (1) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Facult de Mdecine, Universit Paris-Saclay, Le Kremlin-Bictre, France. Facult de Pharmacie, Universit Paris-Saclay, Orsay, France. (2) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Service d'Oncologie Mdicale, Hpital Europen Georges Pompidou, AP-HP, Paris, France. Dpartement d'Innovation Thrapeutique et d'Essais Prcoces (DITEP), Gustave Roussy, Villejuif, France. (3) Facult de Mdecine, Universit Paris-Saclay, Le Kremlin-Bictre, France. Dpartement d'Innovation Thrapeutique et d'Essais Prcoces (DITEP), Gustave Roussy, Villejuif, France. Laboratoire de Recherche Translationnelle en Immunothrapie (LRTI), INSERM U1015 and Centre d'Investigation Clinique BIOTHERIS, INSERM CIC1428, Gustave Roussy, Villejuif, France. (4) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. (5) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. (6) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. (7) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Universit Vita-Salute San Raffaele, Milan, Italy. (8) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Dpartement d'oncologie thoracique et mdicale, Hpitaux Universitaires Paris Seine-Saint-Denis, Hpital Avicenne, AP-HP, Bobigny, France. (9) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. (10) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Facult de Pharmacie, Universit Paris-Saclay, Orsay, France. (11) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Facult de Mdecine, Universit Paris-Saclay, Le Kremlin-Bictre, France. (12) Facult de Mdecine, Universit Paris-Saclay, Le Kremlin-Bictre, France. Dpartement de Mdecine Oncologique, Gustave Roussy, Villejuif, France. (13) Dpartement d'Innovation Thrapeutique et d'Essais Prcoces (DITEP), Gustave Roussy, Villejuif, France. Laboratoire de Recherche Translationnelle en Immunothrapie (LRTI), INSERM U1015 and Centre d'Investigation Clinique BIOTHERIS, INSERM CIC1428, Gustave Roussy, Villejuif, France. (14) AMMICa, UAR 3655/US23, Gustave Roussy, Villejuif, France. (15) AMMICa, UAR 3655/US23, Gustave Roussy, Villejuif, France. Dpartement de Biologie Mdicale et Pathologie Mdicales, Gustave Roussy, Villejuif, France. (16) Dpartement de Biologie Mdicale et Pathologie Mdicales, Gustave Roussy, Villejuif, France. (17) CDI Laboratories Inc., 1 N. Haven Street, Suite B001, Baltimore, MD 21224, USA. (18) CDI Laboratories Inc., 1 N. Haven Street, Suite B001, Baltimore, MD 21224, USA. (19) Dpartement d'Innovation Thrapeutique et d'Essais Prcoces (DITEP), Gustave Roussy, Villejuif, France. Laboratoire de Recherche Translationnelle en Immunothrapie (LRTI), INSERM U1015 and Centre d'Investigation Clinique BIOTHERIS, INSERM CIC1428, Gustave Roussy, Villejuif, France. (20) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. (21) Facult de Mdecine, Universit Paris-Saclay, Le Kremlin-Bictre, France. Dpartement de Mdecine Oncologique, Gustave Roussy, Villejuif, France. (22) Laboratoire d'Immunomonitoring en Oncologie, INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France. Facult de Pharmacie, Universit Paris-Saclay, Orsay, France.
