Predicting developmental relationships of tumor resident and circulating T cells in ovarian cancer

ABSTRACT Characterizing T cell populations and understanding their developmental relationships may help design more effective cancer immunotherapies. We coupled single-cell transcriptomics and T cell receptor (TCR) αβ profiling of intratumoral and peripheral T cells in ovarian cancer patients to identify transcriptional programs and infer their relationship by trajectory and TCR overlap analyses. We proposed a model of differentiation pathway from an intermediate GZMH-expressing CD8 T cell subset found in the blood and tumor that progressively reinforces the exhaustion and tissue residency programs from a CCL4 -expressing cluster towards XCL1 - and CXCL13 -expressing terminally exhausted cells. Inferred cell communication analysis suggests that interaction with CXCL13 -expressing CD4 T cells, which we refer to as Tfh-like cells, sustains the effector function of this intermediate GZMH-expressing CD8 T cell subset. Moreover, our results suggest that Tfh-like cells attract cells expressing GPR183 through the production of its ligand 7α,25 dihydroxycholesterol (7α,25-HC). Finally, we demonstrated that GPR183 is highly expressed in a subset of pre-effector GZMK -expressing CD8 T cells and plasmacytoid dendritic cells. Collectively, our results suggest that Tfh-like cells expressing IL-21 help promote antitumor immunity against ovarian tumors by coordinating the action of immune cells responsive to 7α,25-HC.