Escherichia coli –Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Anne-Gaëlle Goubet (1, 2, 3) , Leonardo Lordello (4) , Carolina Alves Costa Silva (5) , Isabelle Peguillet (6) , Marianne Gazzano (7) , Maxime Descartes Mbogning-Fonkou , Cassandra Thelemaque (2, 3) , Cédric Lebacle (8) , Constance Thibault (9) , François Audenet (9, 10) , Géraldine Pignot (11) , Gwenaelle Gravis (11) , Carole Helissey (12) , Luca Campedel , Morgan Roupret (13) , Evanguelos Xylinas , Idir Ouzaid (14, 10) , Agathe Dubuisson (15, 2) , Marine Mazzenga (2, 15) , Caroline Flament (2, 3) , Pierre Ly , Virginie Marty (2) , Nicolas Signolle (2) , Allan Sauvat (16) , Thomas Sbarrato , Mounia Filahi , Caroline Davin , Gabriel Haddad , Jacques Bou Khalil (17, 18) , Camille Bleriot (3) , François-Xavier Danlos (19) , Garett Dunsmore , Kevin Mulder , Aymeric Silvin , Thibault Raoult (20) , Baptiste Archambaud (21) , Shaima Belhechmi , Ivo Gomperts Boneca , Nadège Cayet , Maryse Moya-Nilges , Adeline Mallet , Romain Daillere , Etienne Rouleau , Camelia Radulescu (22) , Yves Allory (22) , Jacques Fieschi , Mathieu Rouanne (22) , Florent Ginhoux , Gwénaël Le Teuff , Lisa Derosa (3) , Aurélien Marabelle (19) , Jeroen van Dorp , Nick van Dijk , Michiel van der Heijden , Benjamin Besse (23) , Fabrice Andre (20) , Miriam Merad , Guido Kroemer (16) , Jean-Yves Scoazec (24) , Laurence Zitvogel (3) , Yohann Loriot (25)

1 Université Paris-Saclay
2 IGR - Institut Gustave Roussy
3 ITIC - Immunologie anti-tumorale et immunothérapie des cancers
4 OncokappaB (URP_7324) - NF-kappaB, Différenciation et Cancer
5 INTIM - Immunologie intégrative des tumeurs et immunothérapie des cancers
6 Institut Curie [Paris]
7 CIMI - Centre d'Immunologie et des Maladies Infectieuses
8 Petites Molécules de neuroprotection, neurorégénération et remyélinisation
9 HEGP - Hôpital Européen Georges Pompidou [APHP]
10 UPCité - Université Paris Cité
11 Institut Paoli-Calmettes
12 Hôpital d'Instruction des Armées Begin
13 CHU Pitié-Salpêtrière [AP-HP]
14 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
15 UMR 1015 - Immunologie des tumeurs et immunothérapie
16 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
17 MEPHI - Microbes évolution phylogénie et infections
18 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
19 DITEP - Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy]
20 Direction de la recherche clinique [Gustave Roussy]
21 SBE - Service de biostatistique et d'épidémiologie
22 UVSQ - Université de Versailles Saint-Quentin-en-Yvelines
23 Département de médecine oncologique [Gustave Roussy]
24 Département de biologie et pathologie médicales [Gustave Roussy]
25 Oncologie gynécologique

Abstract Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221

Domains: Life Sciences [q-bio]

Anne-Gaëlle Goubet, Leonardo Lordello, Carolina Alves Costa Silva, Isabelle Peguillet, Marianne Gazzano, et al.. Escherichia coli –Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer. Cancer Discovery, 2022, 12 (10), pp.2280-2307. ⟨10.1158/2159-8290.CD-22-0201⟩. ⟨hal-03951702⟩