Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Lawrence P. Andrews; Ashwin Somasundaram; Jessica M. Moskovitz; Andrea L. Szymczak-Workman; Chang Liu; Anthony R. Cillo; Huang Lin; Daniel P. Normolle; Kelly D. Moynihan; Ichiro Taniuchi; Darrell J. Irvine; John M. Kirkwood; Evan J. Lipson; Robert L. Ferris; Tullia C. Bruno; Creg J. Workman; Dario A.A. Vignali

doi:10.1126/sciimmunol.abc2728

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Lawrence P. Andrews, Ashwin Somasundaram, Jessica M. Moskovitz, Andrea L. Szymczak-Workman, Chang Liu, Anthony R. Cillo, Huang Lin, Daniel P. Normolle, Kelly D. Moynihan, Ichiro Taniuchi, Darrell J. Irvine, John M. Kirkwood, Evan J. Lipson, Robert L. Ferris, Tullia C. Bruno, Creg J. Workman, Dario A.A. Vignali

School of Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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 (LAG3^NC) are resistant to PD1 blockade and fail to mount an effective antitumor immune response. Expression of LAG3^NC intrinsically perturbs CD4⁺ T conventional cells (T_convs), 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⁺ T_convs 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.

Original language	English (US)
Article number	eabc2728
Journal	Science Immunology
Volume	5
Issue number	49
DOIs	https://doi.org/10.1126/sciimmunol.abc2728
State	Published - Jul 2020

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Andrews, L. P., Somasundaram, A., Moskovitz, J. M., Szymczak-Workman, A. L., Liu, C., Cillo, A. R., Lin, H., Normolle, D. P., Moynihan, K. D., Taniuchi, I., Irvine, D. J., Kirkwood, J. M., Lipson, E. J., Ferris, R. L., Bruno, T. C., Workman, C. J., & Vignali, D. A. A. (2020). Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Science Immunology, 5(49), Article eabc2728. https://doi.org/10.1126/sciimmunol.abc2728

Andrews, LP, Somasundaram, A, Moskovitz, JM, Szymczak-Workman, AL, Liu, C, Cillo, AR, Lin, H, Normolle, DP, Moynihan, KD, Taniuchi, I, Irvine, DJ, Kirkwood, JM, Lipson, EJ, Ferris, RL, Bruno, TC, Workman, CJ & Vignali, DAA 2020, 'Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding', Science Immunology, vol. 5, no. 49, eabc2728. https://doi.org/10.1126/sciimmunol.abc2728

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title = "Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding",

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 = "Andrews, {Lawrence P.} and Ashwin Somasundaram and Moskovitz, {Jessica M.} and Szymczak-Workman, {Andrea L.} and Chang Liu and Cillo, {Anthony R.} and Huang Lin and Normolle, {Daniel P.} and Moynihan, {Kelly D.} and Ichiro Taniuchi and Irvine, {Darrell J.} and Kirkwood, {John M.} and Lipson, {Evan J.} and Ferris, {Robert L.} and Bruno, {Tullia C.} and Workman, {Creg J.} and Vignali, {Dario A.A.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2020",

month = jul,

doi = "10.1126/sciimmunol.abc2728",

language = "English (US)",

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AU - Somasundaram, Ashwin

AU - Moskovitz, Jessica M.

AU - Szymczak-Workman, Andrea L.

AU - Liu, Chang

AU - Cillo, Anthony R.

AU - Lin, Huang

AU - Normolle, Daniel P.

AU - Moynihan, Kelly D.

AU - Taniuchi, Ichiro

AU - Irvine, Darrell J.

AU - Kirkwood, John M.

AU - Lipson, Evan J.

AU - Ferris, Robert L.

AU - Bruno, Tullia C.

AU - Workman, Creg J.

AU - Vignali, Dario A.A.

PY - 2020/7

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N2 - 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.

AB - 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.

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Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Abstract

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