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

Author:

Nguyen Kim Bich12ORCID,Roerden Malte1,Copeland Christopher J2ORCID,Backlund Coralie M13,Klop-Packel Nory G2,Remba Tanaka1,Kim Byungji1ORCID,Singh Nishant K2,Birnbaum Michael E234ORCID,Irvine Darrell J234,Spranger Stefani1245ORCID

Affiliation:

1. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology

2. Department of Biology, Massachusetts Institute of Technology

3. Department of Biological Engineering, MIT

4. Ragon Institute of MGH, MIT and Harvard

5. Ludwig Center at MIT’s Koch Institute for Integrative Cancer Research

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.

Funder

Melanoma Research Alliance

Lung Cancer Research Foundation

National Cancer Institute

Pew Charitable Trusts

Howard S (1953) and Linda B Stern Career Development Professorship

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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