Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression.

Autor:	Roerden M; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., Castro AB; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK., Cui Y; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA.; Department of Biological Engineering, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., Harake N; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., Kim B; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., Dye J; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., Maiorino L; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., White FM; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA.; Department of Biological Engineering, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA., Irvine DJ; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA.; Department of Biological Engineering, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA.; Ragon Institute at MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA., Litchfield K; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK., Spranger S; Koch Institute for Integrative Cancer Research, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA spranger@mit.edu.; Ragon Institute at MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Nov 09; Vol. 12 (11). Date of Electronic Publication: 2024 Nov 09.
DOI:	10.1136/jitc-2024-010249
Abstrakt:	Background: Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors. Methods: We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms. Data from a large cancer patient cohort was used to study whether NeoAg architecture characteristics found to define tumor immunogenicity in our mouse models are linked to ICB responses in patients with cancer. Results: We demonstrate that concurrent expression and clonality define NeoAg architectures which determine the immunogenicity of individual NeoAg and drive immune evasion of tumors with heterogenous NeoAg expression. Mechanistically, we identified concerted interplays between concurrent T-cell responses induced by cross-presenting dendritic cells (cDC1) mirroring the tumor NeoAg architecture during T-cell priming in the lymph node. Depending on the characteristics and clonality of respective NeoAg, this interplay mutually benefited concurrent T-cell responses or led to competition between T-cell responses to different NeoAg. In tumors with heterogenous NeoAg expression, NeoAg architecture-induced suppression of T-cell responses against branches of the tumor drove immune evasion and caused resistance to ICB. Therapeutic RNA-based vaccination targeting immune-suppressed T-cell responses synergized with ICB to enable control of tumors with subclonal NeoAg expression. A pan-cancer clinical data analysis indicated that competition and synergy between T-cell responses define responsiveness to ICB in patients with cancer. Conclusions: NeoAg architectures modulate the immunogenicity of NeoAg and tumors by dictating the interplay between concurrent T-cell responses mediated by cDC1. Impaired induction of T-cell responses supports immune evasion in tumors with heterogenous NeoAg expression but is amenable to NeoAg architecture-informed vaccination, which in combination with ICB portrays a promising treatment approach for patients with tumors exhibiting high ITH. Competing Interests: Competing interests: SS is an SAB member of Related Sciences, Arcus Biosciences, Ankyra Therapeutics, and Repertoire Immune Medicines. SS is a co-founder of Danger Bio. SS is a consultant for Takeda and Merck, and receives funding for unrelated projects from Leap Therapeutics and iTeos Therapeutics. DJI is a co-founder and consultant for Strand Therapeutics and Elicio Therapeutics. SS’s and DJI’s interests are reviewed and managed under MIT’s policies for potential conflicts of interest. ABC is a consultant for Tempus. KL has a patent on indel burden and CPI response pending, a patent on ctDNA minimal residual disease calling methods; speaker fees from Roche tissue diagnostics and Ellipses pharma; research funding from CRUK TDL/Ono/LifeArc alliance and Genesis Therapeutics; and consulting roles with Monopteros Therapeutics, Kynos Therapeutics and Tempus Labs. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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