Tertiary Lymphoid Structure-B Cells Narrow Regulatory T Cells Impact in Lung Cancer Patients.

Affiliation

Germain C(1)(2)(3)(4)(5), Devi-Marulkar P(3)(4)(5), Knockaert S(3)(4)(5), Biton J(3)(4)(5), Kaplon H(3)(4)(5), Letaïef L(1)(2)(3)(4)(5), Goc J(3)(4)(5), Seguin-Givelet A(2)(6)(7), Gossot D(2)(6), Girard N(8), Validire P(4)(9), Lefèvre M(2)(6)(9), Damotte D(3)(4)(5)(10), Alifano M(3)(4)(5)(11), Lemoine FM(1)(2), Steele KE(12), Teillaud JL(1)(2)(3)(4)(5), Hammond SA(13), Dieu-Nosjean MC(1)(2)(3)(4)(5).
Author information:
(1)Sorbonne Université, UMRS 1135, Faculté de Médecine Sorbonne Université, Paris, France.
(2)Laboratory "Immune Microenvironment and Immunotherapy", INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses Paris
(CIMI-Paris), Paris, France.
(3)Sorbonne Université, UMRS 1138, Paris, France.
(4)Laboratory "Cancer, Immune Control, and Escape", INSERM U1138, Cordeliers Research Center, Paris, France.
(5)Université de Paris, UMRS 1138, Paris, France.
(6)Thoracic Department, Curie-Montsouris Thorax Institute, Institut Mutualiste Montsouris, Paris, France.
(7)Université Sorbonne Paris Nord, Sorbonne Paris Cité, Faculté de Médecine SMBH, Bobigny, France.
(8)Oncology Department, Curie-Montsouris Thorax Institute, Institut Curie, Paris, France.
(9)Department of Pathology, Institut Mutualiste Montsouris, Paris, France.
(10)Department of Pathology, Assistance Publique-Hopitaux de Paris
(AP-HP), Cochin Hospital, Paris, France.
(11)Department of Thoracic Surgery, Assistance Publique-Hopitaux de Paris
(AP-HP), Cochin Hospital, Paris, France.
(12)Oncology Translational Sciences, AstraZeneca, Gaithersburg, MD, United States.
(13)Oncology Research, AstraZeneca, Gaithersburg, MD, United States.

Abstract

The presence of tertiary lymphoid structures (TLS) in the tumor microenvironment is associated with better clinical outcome in many cancers. In non-small cell lung cancer (NSCLC), we have previously showed that a high density of B cells within TLS (TLS-B cells) is positively correlated with tumor antigen-specific antibody responses and increased intratumor CD4+ T cell clonality. Here, we investigated the relationship between the presence of TLS-B cells and CD4+ T cell profile in NSCLC patients. The expression of immune-related genes and proteins on B cells and CD4+ T cells was analyzed according to their relationship to TLS-B density in a prospective cohort of 56 NSCLC patients. We observed that tumor-infiltrating T cells showed marked differences according to TLS-B cell presence, with higher percentages of naïve, central-memory, and activated CD4+ T cells and lower percentages of both immune checkpoint (ICP)-expressing CD4+ T cells and regulatory T cells (Tregs) in the TLS-Bhigh tumors. A retrospective study of 538 untreated NSCLC patients showed that high TLS-B cell density was even able to counterbalance the deleterious impact of high Treg density on patient survival, and that TLS-Bhigh Treglow patients had the best clinical outcomes. Overall, the correlation between the density of TLS-Bhigh tumors with early differentiated, activated and non-regulatory CD4+ T cell cells suggest that B cells may play a central role in determining protective T cell responses in NSCLC patients.

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