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

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.

SUBMITTER: Kasikova L 

PROVIDER: S-EPMC10957872 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature