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

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Escherichia coli–Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer
Cancer Discovery ( IF 28.2 ) Pub Date : 2022-08-05 , DOI: 10.1158/2159-8290.cd-22-0201
Anne-Gaëlle Goubet _{1,

2,

3} , Leonardo Lordello _{1,

3} , Carolina Alves Costa Silva _{1,

2,

3,

4} , Isabelle Peguillet _{1,

3} , Marianne Gazzano _{1,

3,

5} , Maxime Descartes Mbogning-Fonkou _{1,

3} , Cassandra Thelemaque _{1,

3} , Cédric Lebacle ₆ , Constance Thibault ₇ , François Audenet ₈ , Géraldine Pignot ₉ , Gwenaelle Gravis ₁₀ , Carole Helissey ₁₁ , Luca Campedel ₁₂ , Morgan Roupret ₁₃ , Evanguelos Xylinas ₁₄ , Idir Ouzaid ₁₄ , Agathe Dubuisson _{1,

3} , Marine Mazzenga _{1,

3} , Caroline Flament _{1,

3} , Pierre Ly _{1,

3} , Virginie Marty _{1,

15} , Nicolas Signolle _{1,

15} , Allan Sauvat _{1,

16,

17} , Thomas Sbarrato ₁₈ , Mounia Filahi ₁₈ , Caroline Davin ₁₈ , Gabriel Haddad ₁₉ , Jacques Bou Khalil ₁₉ , Camille Bleriot _{1,

3} , François-Xavier Danlos _{1,

2,

3} , Garett Dunsmore _{1,

2,

3} , Kevin Mulder _{1,

2,

3} , Aymeric Silvin _{1,

3} , Thibault Raoult _{1,

20} , Baptiste Archambaud _{1,

21} , Shaima Belhechmi _{1,

21} , Ivo Gomperts Boneca ₂₂ , Nadège Cayet ₂₃ , Maryse Moya-Nilges ₂₃ , Adeline Mallet ₂₃ , Romain Daillere ₂₄ , Etienne Rouleau ₂₅ , Camelia Radulescu ₂₆ , Yves Allory ₂₆ , Jacques Fieschi ₁₈ , Mathieu Rouanne _{1,

2,

3,

27} , Florent Ginhoux _{1,

2,

28,

29} , Gwénaël Le Teuff _{1,

21} , Lisa Derosa _{1,

2,

3} , Aurélien Marabelle _{1,

2,

3,

4,

30} , Jeroen Van Dorp ₃₁ , Nick Van Dijk ₃₂ , Michiel S Van Der Heijden _{31,

32} , Benjamin Besse _{1,

2,

30,

33} , Fabrice Andre _{1,

2,

30,

33,

34} , Miriam Merad _{35,

36,

37,

38,

39} , Guido Kroemer _{1,

16,

17,

40} , Jean-Yves Scoazec _{1,

2,

15,

41} , Laurence Zitvogel _{1,

2,

3,

4} , Yohann Loriot _{1,

2,

30,

33,

34,

42}

Affiliation

Gustave Roussy, Villejuif, France.
Faculté de Médecine, Université Paris-Saclay, Kremlin-Bicêtre, France.
Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France.
Center of Clinical Investigations for In Situ Biotherapies of Cancer (BIOTHERIS), INSERM CIC1428, Villejuif, France.
Sorbonne Université, Inserm, Centre d'immunologie et des maladies infectieuses (CIMI-Paris), Département d'immunologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France.
Urology Department, University Hospital of Bicêtre-Paris Sud-Saclay University, Le Kremlin Bicêtre, Paris, France.
Oncology Department, Hôpital Européen Georges Pompidou, AP-HP, University of Paris, Paris, France.
Department of Urology, Hôpital Européen Georges Pompidou, AP-HP Centre, Université de Paris, Paris, France.
Department of Surgical Oncology 2, Institut Paoli-Calmettes Cancer Center, Marseille, France.
Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, CRCM, Marseille, France.
Military Hospital Begin, Saint-Mandé, France.
Sorbonne Université, AP-HP, hôpital de La Pitié-Salpêtrière, Institut universitaire de cancérologie, département d'oncologie médicale, CLIP2 Galilée, Paris, France.
GRC 5 Predictive Onco-Uro, Sorbonne University, Department of Urology, AP-HP, Pitie-Salpetriere Hospital, Paris, France.
Department of Urology, Bichat-Claude Bernard Hospital, Paris University, Paris France.
Experimental and Translational Pathology Platform (PETRA), AMMICa, INSERM US23/UAR3655, Gustave Roussy, Villejuif, France.
Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale U1138, Université de Paris, Sorbonne Université, Paris, France.
Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
Veracyte, Marseille, France.
Aix-Marseille University, IRD, APHM, MEPHI, Institut Hospitalo-Universitaire Méditerranée Infection, Marseille, France.
Service de Promotion des Etudes Cliniques (SPEC), Gustave Roussy, Université Paris-Saclay, Villejuif, France.
Service de Biostatistiques et d'Epidemiologie, Gustave Roussy, Villejuif, France.
Institut Pasteur, Université de Paris, CNRS UMR2001, INSERM U1306, Unité de Biologie et Génétique de la paroi bactérienne, Paris, France.
Core Facility Ultrastructural BioImaging Core Facility, Institut Pasteur, Paris France.
EverImmune, Gustave Roussy, Villejuif, France.
Department of Medical Biology and Pathology, Cancer Genetics Laboratory, Gustave Roussy, Villejuif, France.
Department of Pathology, Hôpital Foch, UVSQ-Université Paris-Saclay, Suresnes, France.
Department of Urology, Hôpital Foch, UVSQ-Université Paris-Saclay, Suresnes, France.
Singapore Immunology Network (SIgN), A*STAR, Singapore, Singapore.
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Medicine Department, Gustave Roussy, Villejuif, France.
Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands.
Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
INSERM U981, Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, Villejuif, France.
PRISM precision cancer center, Gustave Roussy, Villejuif, France.
The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York.
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Institute for Thoracic Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France.
Early Drug Development Department (DITEP), Gustave Roussy, Villejuif, France.

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

中文翻译：

大肠杆菌特异性 CXCL13 产生 TFH 与新辅助 PD-1 阻断治疗肌层浸润性膀胱癌的临床疗效相关

局限性肌肉浸润性膀胱癌 (MIBC) 患者需要指导免疫检查点阻断剂 (ICB) 新辅助使用的生物标志物。通过分析肿瘤和血液样本，我们发现滤泡辅助 CD4+ T 细胞 (TFH) 是与无进展生存期相关的派姆单抗的最佳治疗靶点之一。TFH 与基线时肿瘤 CD8 和 PD-L1 表达以及派姆单抗后三级淋巴结构的诱导相关。血液中枢记忆 TFH 在肿瘤中积累，并在那里产生 CXCL13，这是一种仅在反应者血浆中发现的趋化因子。膀胱组织中的 IgG4+CD38+ TFH 与临床获益相关。最后，针对尿路上皮侵袭性大肠杆菌的 TFH 和 IgG 决定了三个独立队列中对派姆单抗的临床反应。肿瘤感染与 ICB 免疫调节成功之间的联系应该在更大范围内进行前瞻性评估。意义：在接受新辅助派姆单抗治疗的膀胱癌患者中，产生 TFH 和 IgG 的大肠杆菌特异性 CXCL13 构成了预测临床获益的生物标志物。除了作为生物标志物的作用之外，这种针对大肠杆菌的免疫反应还可用于未来的治疗策略。这篇文章在本期特稿中重点介绍，第 17 页。2221 大肠杆菌可能被用于未来的治疗策略。这篇文章在本期特稿中重点介绍，第 17 页。2221 大肠杆菌可能被用于未来的治疗策略。这篇文章在本期特稿中重点介绍，第 17 页。2221

更新日期：2022-08-05

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