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

Merav Cohen (1, 2, 3) , Amir Giladi (1, 4) , Oren Barboy (1) , Pauline Hamon (3) , Baoguo Li (1) , Mor Zada (1, 2) , Anna Gurevich-Shapiro (1, 2) , Cristian Gabriel Beccaria (5, 6) , Eyal David (1) , Barbara Maier (3) , Mark Buckup (3) , Iris Kamer (7) , Aleksandra Deczkowska (8, 1) , Jessica Le Berichel (3) , Jair Bar (7, 2) , Matteo Iannacone (5, 6) , Amos Tanay (1) , Miriam Merad (3) , Ido Amit (1)

1 Weizmann Institute of Science [Rehovot, Israël]
2 Sackler School of Medicine
3 MSSM - Icahn School of Medicine at Mount Sinai [New York]
4 Hubrecht Institute [Utrecht, Netherlands]
5 IRCCS San Raffaele Scientific Institute [Milan, Italie]
6 UniSR - Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie]
7 Chaim Sheba Medical Center
8 Interactions cerveau-immunité - Brain-immune communication

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.

Domains: Immunology

Merav Cohen, Amir Giladi, Oren Barboy, Pauline Hamon, Baoguo Li, et al.. The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response. Nature Cancer, 2022, 3 (3), pp.303-317. ⟨10.1038/s43018-022-00338-5⟩. ⟨pasteur-03866082⟩