181P - Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer

Background

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. Although, the clinical and biological relevance of TLSs, B cells, plasma cells and humoral adaptive immunity for patients with EOC have been previously reported, the precise immune contexture of developing TLSs, their impact the phenotypic profile of intratumoral T cells, and their influence on sensitivity to immunotherapy remain to be investigated in detail.

Methods

We harnessed spatial transcriptomics, multiplex immunofluorescence microscopy, and flow cytometry to characterize TLSs in patients with high-grade serous ovarian carcinoma (HGSOC), non-small cell lung carcinoma (NSCLC) and experimental mouse models.

Results

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) were 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. Converesely, CD8⁺ T cells from immunologically hot tumors like non-small cell lung carcinoma (NSCLC) were enriched in ICI-responsive TCF1⁺ PD1⁺ T cells. Spatial B-cell profiling identified patterns of in situ maturation and differentiation that were associated with mTLSs. Moreover, B-cell depletion promoted signs of a dysfunctional CD8⁺ T cell compartment among tumor-infiltrating lymphocytes from freshly isolated HGSOC and NSCLC biopsies.

Conclusions

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 are 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.

Legal entity responsible for the study

The authors.

Funding

Sotio Biotech.

Disclosure

All authors have declared no conflicts of interest.