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Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression

Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been...

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Autores principales: Nguyen, Kim Bich, Roerden, Malte, Copeland, Christopher J, Backlund, Coralie M, Klop-Packel, Nory G, Remba, Tanaka, Kim, Byungji, Singh, Nishant K, Birnbaum, Michael E, Irvine, Darrell J, Spranger, Stefani
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425174/
https://www.ncbi.nlm.nih.gov/pubmed/37548358
http://dx.doi.org/10.7554/eLife.85263
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author Nguyen, Kim Bich
Roerden, Malte
Copeland, Christopher J
Backlund, Coralie M
Klop-Packel, Nory G
Remba, Tanaka
Kim, Byungji
Singh, Nishant K
Birnbaum, Michael E
Irvine, Darrell J
Spranger, Stefani
author_facet Nguyen, Kim Bich
Roerden, Malte
Copeland, Christopher J
Backlund, Coralie M
Klop-Packel, Nory G
Remba, Tanaka
Kim, Byungji
Singh, Nishant K
Birnbaum, Michael E
Irvine, Darrell J
Spranger, Stefani
author_sort Nguyen, Kim Bich
collection PubMed
description Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been fully elucidated. Mounting clinical evidence suggests that the clonal status of neoantigens (NeoAg) impacts the anti-tumor T cell response. High intratumor heterogeneity (ITH), where the majority of NeoAgs are expressed subclonally, is correlated with poor clinical response to CBT and poor infiltration with tumor-reactive T cells. However, the mechanism by which ITH blunts tumor-reactive T cells is unclear. We developed a transplantable murine lung cancer model to characterize the immune response against a defined set of NeoAgs expressed either clonally or subclonally to model low or high ITH, respectively. Here we show that clonal expression of a weakly immunogenic NeoAg with a relatively strong NeoAg increased the immunogenicity of tumors with low but not high ITH. Mechanistically we determined that clonal NeoAg expression allowed cross-presenting dendritic cells to acquire and present both NeoAgs. Dual NeoAg presentation by dendritic cells was associated with a more mature DC phenotype and a higher stimulatory capacity. These data suggest that clonal NeoAg expression can induce more potent anti-tumor responses due to more stimulatory dendritic cell:T cell interactions. Therapeutic vaccination targeting subclonally expressed NeoAgs could be used to boost anti-tumor T cell responses.
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spelling pubmed-104251742023-08-15 Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression Nguyen, Kim Bich Roerden, Malte Copeland, Christopher J Backlund, Coralie M Klop-Packel, Nory G Remba, Tanaka Kim, Byungji Singh, Nishant K Birnbaum, Michael E Irvine, Darrell J Spranger, Stefani eLife Cancer Biology Cancer immunotherapies, in particular checkpoint blockade immunotherapy (CBT), can induce control of cancer growth, with a fraction of patients experiencing durable responses. However, the majority of patients currently do not respond to CBT and the molecular determinants of resistance have not been fully elucidated. Mounting clinical evidence suggests that the clonal status of neoantigens (NeoAg) impacts the anti-tumor T cell response. High intratumor heterogeneity (ITH), where the majority of NeoAgs are expressed subclonally, is correlated with poor clinical response to CBT and poor infiltration with tumor-reactive T cells. However, the mechanism by which ITH blunts tumor-reactive T cells is unclear. We developed a transplantable murine lung cancer model to characterize the immune response against a defined set of NeoAgs expressed either clonally or subclonally to model low or high ITH, respectively. Here we show that clonal expression of a weakly immunogenic NeoAg with a relatively strong NeoAg increased the immunogenicity of tumors with low but not high ITH. Mechanistically we determined that clonal NeoAg expression allowed cross-presenting dendritic cells to acquire and present both NeoAgs. Dual NeoAg presentation by dendritic cells was associated with a more mature DC phenotype and a higher stimulatory capacity. These data suggest that clonal NeoAg expression can induce more potent anti-tumor responses due to more stimulatory dendritic cell:T cell interactions. Therapeutic vaccination targeting subclonally expressed NeoAgs could be used to boost anti-tumor T cell responses. eLife Sciences Publications, Ltd 2023-08-07 /pmc/articles/PMC10425174/ /pubmed/37548358 http://dx.doi.org/10.7554/eLife.85263 Text en © 2023, Nguyen et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Nguyen, Kim Bich
Roerden, Malte
Copeland, Christopher J
Backlund, Coralie M
Klop-Packel, Nory G
Remba, Tanaka
Kim, Byungji
Singh, Nishant K
Birnbaum, Michael E
Irvine, Darrell J
Spranger, Stefani
Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
title Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
title_full Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
title_fullStr Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
title_full_unstemmed Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
title_short Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
title_sort decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425174/
https://www.ncbi.nlm.nih.gov/pubmed/37548358
http://dx.doi.org/10.7554/eLife.85263
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