Franken and Bila et al. demonstrated that single-dose neoadjuvant anti-PD-L1 immunotherapy in patients with HNSCC led to intratumoral expansion of CD8+ Tem, Trm, and Tex cells, and the addition of anti-CTLA-4 expanded CD4+ T cells in close vicinity to CD8+ T cells. The expanded CD4+ and CD8+ T cells co-localized with plasma cells and dendritic cells expressing antigen presentation and T cell homing genes. T cell receptor tracing suggested that anti-CTLA-4-induced naive/central-memory CD4+ T cells trafficked from tumor-draining lymph nodes to the tumor, wherein these T cells differentiated into CD4+ Tem or Th1 phenotypes.
Contributed by Shishir Pant
ABSTRACT: Cancer patients often receive a combination of antibodies targeting programmed death-ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen-4 (CTLA4). We conducted a window-of-opportunity study in head and neck squamous cell carcinoma (HNSCC) to examine the contribution of anti-CTLA4 to anti-PD-L1 therapy. Single-cell profiling of on- versus pre-treatment biopsies identified T cell expansion as an early response marker. In tumors, anti-PD-L1 triggered the expansion of mostly CD8(+) T cells, whereas combination therapy expanded both CD4(+) and CD8(+) T cells. Such CD4(+) T cells exhibited an activated T helper 1 (Th1) phenotype. CD4(+) and CD8(+) T cells co-localized with and were surrounded by dendritic cells expressing T cell homing factors or antibody-producing plasma cells. T cell receptor tracing suggests that anti-CTLA4, but not anti-PD-L1, triggers the trafficking of CD4(+) naive/central-memory T cells from tumor-draining lymph nodes (tdLNs), via blood, to the tumor wherein T cells acquire a Th1 phenotype. Thus, CD4(+) T cell activation and recruitment from tdLNs are hallmarks of early response to anti-PD-L1 plus anti-CTLA4 in HNSCC.
Author Info: (1) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (2) Laboratory of Exp
Author Info: (1) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (2) Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Department of General Medical Oncology, UZ Leuven, 3000 Leuven, Belgium; Department of Oral and Maxillofacial Surgery, UZ Leuven, Leuven 3000, Belgium. (3) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (4) Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), Leuven 3000, Belgium. (5) Department of Oral and Maxillofacial Surgery, UZ Leuven, Leuven 3000, Belgium. (6) Digestive Oncology, KU Leuven, UZ Leuven, Leuven 3000, Belgium. (7) Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), Leuven 3000, Belgium. (8) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (9) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (10) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (11) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (12) Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Department of General Medical Oncology, UZ Leuven, 3000 Leuven, Belgium. (13) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (14) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium. (15) Department of Imaging and Pathology, KU Leuven, UZ Leuven, Leuven 3000, Belgium. (16) Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), Leuven 3000, Belgium; Department of Biomolecular Medicine, UZ Ghent, Ghent 9052, Belgium. (17) Otorhinolaryngology, Head and Neck Surgery, Leuven 3000, Belgium. (18) Otorhinolaryngology, Head and Neck Surgery, Leuven 3000, Belgium. (19) Otorhinolaryngology, Head and Neck Surgery, Leuven 3000, Belgium; Department of Oncology, Section Head and Neck Oncology, Leuven 3000, Belgium. (20) Digestive Oncology, KU Leuven, UZ Leuven, Leuven 3000, Belgium. (21) Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), Leuven 3000, Belgium. (22) Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, China. (23) Digestive Oncology, KU Leuven, UZ Leuven, Leuven 3000, Belgium. (24) Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), Leuven 3000, Belgium. (25) Laboratory of Experimental Oncology (LEO), Department of Oncology, KU Leuven, 3000 Leuven, Belgium; Department of General Medical Oncology, UZ Leuven, 3000 Leuven, Belgium. Electronic address: paul.clement@uzleuven.be. (26) Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven 3000, Belgium; VIB Center for Cancer Biology, Leuven 3000, Belgium; KU Leuven Institute for Single Cell Omics (LISCO), Leuven 3000, Belgium. Electronic address: diether.lambrechts@kuleuven.be.
