The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response

Merav Cohen, Amir Giladi, Oren Barboy, Pauline Hamon, Baoguo Li, Mor Zada, Anna Gurevich-Shapiro, Cristian Gabriel Beccaria, Eyal David, Barbara B. Maier, Mark Buckup, Iris Kamer, Aleksandra Deczkowska, Jessica Le Berichel, Jair Bar, Matteo Iannacone, Amos Tanay, Miriam Merad, Ido Amit

Research output: Contribution to journalArticlepeer-review

Abstract

Despite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4+PD-1+CXCL13+ T cells are a major interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells. Reconstitution of Tht cells in vitro and in an ovalbumin-specific αβ TCR CD4+ T-cell mouse model, shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells presenting tumor antigens, and that their function is important for harnessing the antitumor response of anti-PD-1 treatment. Our molecular and functional findings support the modulation of Tht–dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy.

Original languageEnglish
Pages (from-to)303-317
Number of pages15
JournalNature Cancer
Volume3
Issue number3
DOIs
StatePublished - Mar 2022

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