Cohen, Giladi, and Barboy et al. used scRNAseq and sequencing of physically interacting cells (PIC-seq) to systematically characterize the cell landscape in the TME to determine if a functional interacting T–myeloid cell signature was present. CD4+PD-1+CXCL13+ T cells (T-helper tumor [Tht] cells), and not CD8+ T cells, preferentially formed interactions with LAMP+ mature regulatory DCs, and were clonally expanded in human NSCLC lesions, but not in normal tissue. Tht cells were tumor-specific (primed by tumor antigen-presenting DCs in tumor-draining LNs), conserved across several tumor types, and required for an antitumor response to anti-PD-1.
Contributed by Katherine Turner
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 __ 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.
Author Info: (1) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. meravcohen@tauex.tau.ac.il. Department of Clinical Microbiology and Immunology, Sackler School of Medi
Author Info: (1) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. meravcohen@tauex.tau.ac.il. Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel. meravcohen@tauex.tau.ac.il. Department of Oncological Sciences, The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. meravcohen@tauex.tau.ac.il. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. meravcohen@tauex.tau.ac.il. (2) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. Oncode Institute, Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Utrecht, the Netherlands. (3) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Oncological Sciences, The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel. (7) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel. Division of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. (8) Division of Immunology, Transplantation and Infectious Diseases and Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy. (9) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. (10) Department of Oncological Sciences, The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Department of Oncological Sciences, The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel. (13) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. Brain-Immune Communication Laboratory, Department of Immunology and Neuroscience, Institute Pasteur, Paris, France. (14) Department of Oncological Sciences, The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel. Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel. (16) Division of Immunology, Transplantation and Infectious Diseases and Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, and Vita-Salute San Raffaele University, Milan, Italy. (17) Department of Computer Science and Applied Mathematics, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. amos.tanay@weizmann.ac.il. (18) Department of Oncological Sciences, The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. miriam.merad@mssm.edu. (19) Department of Immunology, Weizmann Institute of Science, Rehovot, Israel. ido.amit@weizmann.ac.il.
