To assess whether LAG3 shedding by metalloproteases ADAM10 and ADAM17 plays a role in responsiveness to PD-1 blockade, Andrews et al. evaluated the effect of anti-PD-1 in mice expressing a non-cleavable form of LAG3 (LAG3NC) in T cells. In four tumor models, mice expressing LAG3NC were resistant to PD-1 inhibition due to selective loss and decreased function of conventional intratumoral CD4+Foxp3- T cells, resulting in failure to provide CD8+ T cell help. A high LAG3/low ADAM10 ratio correlated with poor prognosis and increased disease progression in patients with several tumor types (HNSCC, melanoma, and skin).
Contributed by Katherine Turner
ABSTRACT: Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene-3 (LAG3) signaling is regulated by a disintegrin and metalloprotease domain-containing protein-10 (ADAM10)- and ADAM17-mediated cell surface shedding. Here, we show that mice expressing a metalloprotease-resistant, noncleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3NC intrinsically perturbs CD4+ T conventional cells (Tconvs), limiting their capacity to provide CD8+ T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4+ Tconvs in the peripheral blood of patients with head and neck squamous cell carcinoma, which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (2) Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (2) Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (3) Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (4) Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (5) Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. (6) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan. (9) Howard Hughes Medical Institute, Chevy Chase, MD, USA. (10) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11) Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (12) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dvignali@pitt.edu.
