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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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

Funding

FundersFunder number
Helen and Martin Kimmel
Kahn FoundationR01 CA254104, R01 CA257195
Seed Networks for the Human Cell Atlas
Wolfson Foundation and Family Charitable Trust
Yad Hanadiv Foundation
Howard Hughes Medical Institute
National Cancer InstituteR01CA257195, R01CA254104
Samuel Waxman Cancer Research Foundation
Achelis Foundation724824
Melanoma Research Alliance509044
Icahn School of Medicine at Mount Sinai
Merck KGaA
European Research Council724471-HemTree2.0
Deutsche ForschungsgemeinschaftSFB/TRR167
Israel Science Foundation
Israeli Centers for Research Excellence

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