The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Jean-Eudes Fahrner (1) , Imran Lahmar , Anne-Gaëlle Goubet , Yacine Haddad , Agathe Carrier , Marine Mazzenga , Damien Drubay , Carolina Alves Costa Silva , Eric de Sousa , Cassandra Thelemaque , Cléa Melenotte , Agathe Dubuisson , Arthur Geraud , Gladys Ferrere , Roxanne Birebent , Camille Bigenwald , Marion Picard , Luigi Cerbone , Joana Lérias , Ariane Laparra , Alice Bernard-Tessier , Benoît Kloeckner , Marianne Gazzano , François-Xavier Danlos , Safae Terrisse , Eugenie Pizzato , Caroline Flament , Pierre Ly , Eric Tartour , Nadine Benhamouda , Lydia Meziani , Abdelhakim Ahmed-Belkacem , Makoto Miyara , Guy Gorochov , Fabrice Barlesi , Alexandre Trubert , Benjamin Ungar , Yeriel Estrada , Caroline Pradon , Emmanuelle Gallois , Fanny Pommeret , Emeline Colomba , Pernelle Lavaud , Marc Deloger , Nathalie Droin , Eric Deutsch , Bertrand Gachot , Jean-Philippe Spano , Mansouria Merad , Florian Scotté , Aurélien Marabelle , Frank Griscelli , Jean-Yves Blay , Jean-Charles Soria , Miriam Merad , Fabrice André , Juliette Villemonteix , Mathieu Chevalier , Sophie Caillat-Zucman , Florence Fenollar (2, 3) , Emma Guttman-Yassky , Odile Launay , Guido Kroemer , Bernard La Scola (4, 3) , Markus Maeurer , Lisa Derosa , Laurence Zitvogel (5, 6)

1 Université Paris-Saclay
2 VITROME - Vecteurs - Infections tropicales et méditerranéennes
3 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
4 MEPHI - Microbes évolution phylogénie et infections
5 AP-HP. Université Paris Saclay
6 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie

Abstract Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants. Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873

Domains: Life Sciences [q-bio]; Microbiology and Parasitology; Bacteriology; Life Sciences [q-bio]; Microbiology and Parasitology; Virology; Life Sciences [q-bio]; Microbiology and Parasitology; Parasitology; Life Sciences [q-bio]; Human health and pathology; Cardiology and cardiovascular system; Life Sciences [q-bio]; Human health and pathology; Emerging diseases; Life Sciences [q-bio]; Human health and pathology; Infectious diseases

Jean-Eudes Fahrner, Imran Lahmar, Anne-Gaëlle Goubet, Yacine Haddad, Agathe Carrier, et al.. The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals. Cancer Discovery, 2022, 12 (4), pp.958-983. ⟨10.1158/2159-8290.CD-21-1441⟩. ⟨hal-03678977⟩