. Author manuscript; available in PMC: 2022 Oct 1.

Published in final edited form as: Nat Rev Drug Discov. 2022 Feb 1;21(4):261–282. doi: 10.1038/s41573-021-00387-y

Table 2. Classification of neoantigens by potential functional impact.

	Guarding neoantigens		Restrained neo antigens	Ignored neoantigens
Characteristic features	Supreme neoantigens with a strong antigenicity driving early priming and rapid expansion of neoantigen specific cytotoxic T cells	neoantigens cross-recognised by pre-formed memory T cells induced by heterologous immunity	Neoantigens that are immunogenic in the immunotherapy-naïve host and induce PD1+ memory T cells which proliferate and expand under ICB	Neoantigens which do not induce a relevant immune response in the tumour-bearing host but are able to drive tumour immunity once memory effector T cells are induced by vaccination,
Frequency	Extremely rare	<2% of all mutations	<2% of all mutations	15-25% of all mutations
Examples in mice	DDX5⁸⁵, SPTBN2⁸³	SIY⁸⁷	LAMA4^6,53, ITGB1⁵³	KIF18b^23,102
Examples in human	n.a.	MUC16⁵⁰	ATR⁵	RETSAT^19,20
Clinical relevance	Prognostically relevant drivers of anti-tumour immunity in the immunotherapy-naïve host.		Inactive due to immunosuppression in immunotherapy-naïve host. Main drivers of clinical ICB activity.	No impact on tumour control in immunotherapy-naïve or ICB-treated host. Confer poly-specific anti-tumour T-cell control by broadening the repertoire of tumour-specific T cells upon neoantigen vaccination.