Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte activation gene–3 (LAG3) signaling is regulated...
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science (AAAS)
2021
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| Online Access: | https://hdl.handle.net/1721.1/133023 |
| _version_ | 1826198593576370176 |
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| author | Andrews, Lawrence P Somasundaram, Ashwin Moskovitz, Jessica M Szymczak-Workman, Andrea L Liu, Chang Cillo, Anthony R Lin, Huang Normolle, Daniel P Moynihan, Kelly Dare Taniuchi, Ichiro Irvine, Darrell J Kirkwood, John M Lipson, Evan J Ferris, Robert L Bruno, Tullia C Workman, Creg J Vignali, Dario AA |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Andrews, Lawrence P Somasundaram, Ashwin Moskovitz, Jessica M Szymczak-Workman, Andrea L Liu, Chang Cillo, Anthony R Lin, Huang Normolle, Daniel P Moynihan, Kelly Dare Taniuchi, Ichiro Irvine, Darrell J Kirkwood, John M Lipson, Evan J Ferris, Robert L Bruno, Tullia C Workman, Creg J Vignali, Dario AA |
| author_sort | Andrews, Lawrence P |
| collection | MIT |
| description | Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works 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. |
| first_indexed | 2024-09-23T11:07:13Z |
| format | Article |
| id | mit-1721.1/133023 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:07:13Z |
| publishDate | 2021 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1330232022-09-27T17:17:09Z Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding Andrews, Lawrence P Somasundaram, Ashwin Moskovitz, Jessica M Szymczak-Workman, Andrea L Liu, Chang Cillo, Anthony R Lin, Huang Normolle, Daniel P Moynihan, Kelly Dare Taniuchi, Ichiro Irvine, Darrell J Kirkwood, John M Lipson, Evan J Ferris, Robert L Bruno, Tullia C Workman, Creg J Vignali, Dario AA Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works 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. NIH (Grant EB022433) 2021-10-18T14:57:59Z 2021-10-18T14:57:59Z 2020 2021-09-03T17:06:04Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133023 Andrews, Lawrence P, Somasundaram, Ashwin, Moskovitz, Jessica M, Szymczak-Workman, Andrea L, Liu, Chang et al. 2020. "Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding." Science Immunology, 5 (49). en 10.1126/SCIIMMUNOL.ABC2728 Science Immunology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Andrews, Lawrence P Somasundaram, Ashwin Moskovitz, Jessica M Szymczak-Workman, Andrea L Liu, Chang Cillo, Anthony R Lin, Huang Normolle, Daniel P Moynihan, Kelly Dare Taniuchi, Ichiro Irvine, Darrell J Kirkwood, John M Lipson, Evan J Ferris, Robert L Bruno, Tullia C Workman, Creg J Vignali, Dario AA Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding |
| title | Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding |
| title_full | Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding |
| title_fullStr | Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding |
| title_full_unstemmed | Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding |
| title_short | Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding |
| title_sort | resistance to pd1 blockade in the absence of metalloprotease mediated lag3 shedding |
| url | https://hdl.handle.net/1721.1/133023 |
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