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

Abstract

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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Article and author information

Author details

  1. Kim Bich Nguyen

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2269-6809
  2. Malte Roerden

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Christopher J Copeland

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6882-3359
  4. Coralie M Backlund

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. Nory G Klop-Packel

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Tanaka Remba

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. Byungji Kim

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8131-5255
  8. Nishant K Singh

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  9. Michael E Birnbaum

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    Michael E Birnbaum, is an equity holder in 3T Biosciences, and is a co-founder, equity holder, and consultant of Kelonia Therapeutics and Abata Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2281-3518
  10. Darrell J Irvine

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  11. Stefani Spranger

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    spranger@mit.edu
    Competing interests
    Stefani Spranger, is a SAB member for Related Sciences,Arcus Biosciences, Ankyra Therapeutics and Venn Therapeutics. S.S. is a co-founder ofDanger Bio. S.S. is a consultant for TAKEDA, Merck, Tango Therapeutics, Dragonfly andRibon Therapeutics and receives funding for unrelated projects from Leap Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3257-4546

Funding

Melanoma Research Alliance

  • Stefani Spranger

Lung Cancer Research Foundation

  • Stefani Spranger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Pramod K Srivastava, UConn Health, United States

Ethics

Animal experimentation: All experimental animal procedures were approved by the Committee on Animal Care (CAC/IACUC) at MIT.

Version history

  1. Received: November 30, 2022
  2. Preprint posted: December 19, 2022 (view preprint)
  3. Accepted: August 6, 2023
  4. Accepted Manuscript published: August 7, 2023 (version 1)
  5. Version of Record published: August 14, 2023 (version 2)
  6. Version of Record updated: November 29, 2023 (version 3)

Copyright

© 2023, Nguyen et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kim Bich Nguyen
  2. Malte Roerden
  3. Christopher J Copeland
  4. Coralie M Backlund
  5. Nory G Klop-Packel
  6. Tanaka Remba
  7. Byungji Kim
  8. Nishant K Singh
  9. Michael E Birnbaum
  10. Darrell J Irvine
  11. Stefani Spranger
(2023)
Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression
eLife 12:e85263.
https://doi.org/10.7554/eLife.85263

Share this article

https://doi.org/10.7554/eLife.85263

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