Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Lenka Kašíková, Jana Raková, Michal Hensler, Tereza Láníčková, Jana Tománková, Josef Pasulka, Jana Drozenová, Kateřina Mojžíšová, Anna Fialová, Sarka Vosahlikova, Ján Laco, Aleš Ryška, Pavel Dundr, Roman Kocián, Tomáš Brtnický, Petr Škapa, Linda Čapková, Marek Kovář, Jan Procházka, Ivan Práznovec, Vladimír Koblížek, Alice Tašková, Hisashi Tanaka, Robert Lischke, Fernando Casas Mendez, J Vachtenheim, Viola Heinzelmann‐Schwarz, Francis Jacob, Iain A. McNeish, Michal Halaška, Lukáš Rob, David Cibula, Sandra Oršulić, Lorenzo Galluzzi, Radek Špíšek, Jitka Fučíková
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 (T EFF ) 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.