Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer

Lenka Kasikova, Jana Rakova, Michal Hensler, Tereza Lanickova, Jana Tomankova, Josef Pasulka, Jana Drozenova, Katerina Mojzisova, Anna Fialova, Sarka Vosahlikova, Jan Laco, Ales Ryska, Pavel Dundr, Roman Kocian, Tomas Brtnicky, Petr Skapa, Linda Capkova, Marek Kovar, Jan Prochazka, Ivan Praznovec, Vladimir Koblizek, Alice Taskova, Hisashi Tanaka, Robert Lischke, Fernando Casas Mendez, Jiri Vachtenheim, Viola Heinzelmann-Schwarz, Francis Jacob, Iain A. McNeish, Michal J. Halaska, Lukas Rob, David Cibula, Sandra Orsulic, Lorenzo Galluzzi, Radek Spisek and Jitka Fucikova ()
Additional contact information
Lenka Kasikova: Sotio Biotech a.s.
Jana Rakova: Sotio Biotech a.s.
Michal Hensler: Sotio Biotech a.s.
Tereza Lanickova: Sotio Biotech a.s.
Jana Tomankova: Sotio Biotech a.s.
Josef Pasulka: Sotio Biotech a.s.
Jana Drozenova: 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady
Katerina Mojzisova: Sotio Biotech a.s.
Anna Fialova: Sotio Biotech a.s.
Sarka Vosahlikova: Sotio Biotech a.s.
Jan Laco: Faculty of Medicine and University Hospital Hradec Kralove
Ales Ryska: Faculty of Medicine and University Hospital Hradec Kralove
Pavel Dundr: Charles University and General University Hospital
Roman Kocian: Charles University
Tomas Brtnicky: University Hospital Bulovka
Petr Skapa: Charles University and University Hospital Motol
Linda Capkova: Charles University and University Hospital Motol
Marek Kovar: Institute of Microbiology of the Czech Academy of Sciences
Jan Prochazka: Institute of Molecular Genetics of the Czech Academy of Sciences
Ivan Praznovec: Faculty of Medicine and University Hospital Hradec Kralove
Vladimir Koblizek: University Hospital Hradec Kralove
Alice Taskova: Charles University, 3rd Faculty of Medicine and Thomayer University Hospital
Hisashi Tanaka: Cedars-Sinai Medical Center
Robert Lischke: Charles University and University Hospital Motol
Fernando Casas Mendez: Charles University and University Hospital Motol
Jiri Vachtenheim: Charles University and University Hospital Motol
Viola Heinzelmann-Schwarz: University Hospital Basel and University of Basel
Francis Jacob: University Hospital Basel and University of Basel
Iain A. McNeish: Imperial College London
Michal J. Halaska: 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady
Lukas Rob: 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady
David Cibula: Charles University
Sandra Orsulic: Los Angeles
Lorenzo Galluzzi: Weill Cornell Medical College
Radek Spisek: Sotio Biotech a.s.
Jitka Fucikova: Sotio Biotech a.s.

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in various cohorts of patients with cancer, reflecting their contribution to the development of tumor-targeting immunity. Here, we demonstrate that high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs (mTLS) as forming only in 16% of HGSOCs with relatively elevated tumor mutational burden (TMB) are associated with an increased intratumoral density of CD8+ effector T (TEFF) cells and TIM3+PD1+, hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells. Conversely, CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) are enriched in ICI-responsive TCF1+ PD1+ T cells. Spatial B-cell profiling identifies patterns of in situ maturation and differentiation associated with mTLSs. Moreover, B-cell depletion promotes signs of a dysfunctional CD8+ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies. Taken together, our data demonstrate that – at odds with NSCLC – HGSOC is associated with a low density of follicular helper T cells and thus develops a limited number of mTLS that might be insufficient to preserve a ICI-sensitive TCF1+PD1+ CD8+ T cell phenotype. These findings point to key quantitative and qualitative differences between mTLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative immunotherapies for patients with HGSOC.

Date: 2024
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DOI: 10.1038/s41467-024-46873-w

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