Mature tertiary lymphoid structures are associated with clinically relevant T cell exhaustion in ovarian cancer

Intratumoral tertiary lymphoid structures (TLSs) have been associated with improved outcome in a variety of cancer patient cohorts, reflecting the key role of TLSs in the initiation of tumor-targeting immunity. Here, we demonstrate that human high-grade serous ovarian carcinoma (HGSOC) contains distinct immune aggregates with varying degrees of organization and maturation. Specifically, mature TLSs as forming in HGSOCs with relatively elevated tumor mutational burden (TMB) were associated not only with an increased intratumoral density of CD8+ effector T (TEFF) cells but also with higher amounts of terminally exhausted (TIM-3+PD-1+), and hence poorly immune checkpoint inhibitor (ICI)-sensitive, CD8+ T cells as compared to CD8+ T cells from immunologically hot tumors like non-small cell lung carcinoma. Spatial B-cell profiling identified patterns of in situ maturation and differentiation that were associated with mature TLSs. Moreover, B cell depletion promoted terminal exhaustion in the CD8+ T cell compartment of tumor-infiltrating lymphocytes freshly isolated from HGSOC biopsies, suggesting a key role for intratumoral B cells in the preservation of TEFF functions. In line with previous findings, the clinical benefits of dendritic cell (DC)-based immunotherapy (DCVAC) were more pronounced in HGSOC patients with reduced prevalence of mature TLSs and terminally exhausted CD8+ T cells. Taken together, our data demonstrate that CD8+ T cells associated with mature TLSs as elicited by a relatively high TMB in the HGSOC microenvironment are largely exhausted and hence irresponsive to conventional ICIs. These findings point to key numerical and functional differences between mature TLSs in ICI-responsive vs ICI-irresponsive neoplasms that may guide the development of alternative ICI-based immunotherapies for patients with HGSOC.