In patients with stage III/IVa HNSCC treated with neoadjuvant nivolumab and combinations with relatlimab or ipilimumab, combination treatments improved pathologic responses over monotherapy. Pathologic responders to Nivo+IpI or Nivo+Rela showed distinct CD8+ TIL profiles at baseline, which could help to stratify patients for treatment selection. Nivo+Rela mainly targeted exhausted CD8+ TILs with IFN-I-stimulated gene signatures, promoting their transition to an effector profile, and resulting in increased TCR diversity and TCR sharing among different transcriptional states. Meanwhile, Nivo+Ipi mainly activated and expanded pre-existing effector memory and resident memory TILs.
ABSTRACT: We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8(+) tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8(+) TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (T(EM)/T(RM)). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing T(EM)/T(RM) CD8(+) TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8(+) T cells.
Author Info: (1) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Molecular Genetics and Development Biology Grad
Author Info: (1) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Molecular Genetics and Development Biology Graduate Program, University of Pittsburgh, Pittsburgh, PA, USA. (2) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (3) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (4) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. (5) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (6) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (7) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (8) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. (9) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (10) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Biostatistics Facility, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (11) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany. (12) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, NYU Grossman School of Medicine, New York, NY, USA. (13) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (14) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (15) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (16) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. (17) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Molecular Genetics and Development Biology Graduate Program, University of Pittsburgh, Pittsburgh, PA, USA. (18) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (19) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (20) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (21) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (22) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (23) UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: lazar.vujanovic@pitt.edu. (24) UNC Lineberger Comprehensive Cancer Center, UNC Health Care System, Chapel Hill, NC, USA. Electronic address: robert_ferris@med.unc.edu.
