Li et al. tested the 209 highest-ranking predicted neoepitopes from the ICB-unresponsive Lewis Lung Carcinoma, and only one neoantigen (mRIOK1) was validated by mass cytometry-based MHC-I tetramer staining. Although mRIOK1-specific granzyme-B+ CD8+ T cells in tumors expanded, they remained phenotypically and functionally exhausted after anti-PD-1 or anti-CTLA-4 therapy. Combination therapy induced a stem-like phenotype and more IFNγ and TNFα production, but did not induce tumor regression. Neoantigen vaccination increased mRIOK1- specific CD8+ T cells in tumors, but alone or combined with ICB, did not improve the antitumor response.
Contributed by Paula Hochman
ABSTRACT: Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti-PD-1 and anti-CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8(+) T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen-specific CD8(+) T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8(+) tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8(+) TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8(+) TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8(+) TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.
Author Info: (1) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; enewell@fredhutch.org shaminli@fredhutch.org. (2) Vaccine and Infectious Di
Author Info: (1) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; enewell@fredhutch.org shaminli@fredhutch.org. (2) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. ImmunoSCAPE, Pte Ltd, Singapore, 228208 Singapore. (3) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. (4) Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. Department of Genome Sciences, University of Washington, Seattle, WA 98195. Medical Scientist Training Program, University of Washington, Seattle, WA 98195. (5) National Centre for Asbestos Related Disease, Faculty of Health and Medical Science, University of Western Australia, 6009 Perth, Australia. (6) National Centre for Asbestos Related Disease, Faculty of Health and Medical Science, University of Western Australia, 6009 Perth, Australia. (7) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. (8) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. (9) National Centre for Asbestos Related Disease, Faculty of Health and Medical Science, University of Western Australia, 6009 Perth, Australia. Department of Respiratory Medicine, Sir Charles Gairdner Hospital, 6009 Perth, Australia. Institute for Respiratory Health, University of Western Australia, 6009 Perth, Australia. (10) Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109. Department of Genome Sciences, University of Washington, Seattle, WA 98195. (11) National Centre for Asbestos Related Disease, Faculty of Health and Medical Science, University of Western Australia, 6009 Perth, Australia. (12) National Centre for Asbestos Related Disease, Faculty of Health and Medical Science, University of Western Australia, 6009 Perth, Australia. (13) Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; enewell@fredhutch.org shaminli@fredhutch.org.
