Peripheral vaccination-induced brain-resident memory CD8+ T cells durably protect mice against intracranial malignancy
Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
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Research Article Immunology Neuroscience Oncology

Peripheral vaccination-induced brain-resident memory CD8+ T cells durably protect mice against intracranial malignancy

Abstract

Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.

Authors

Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty

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Figure 2

TRM persist in the brain following intracranial tumor challenge.

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TRM persist in the brain following intracranial tumor challenge. (A) Exp...
(A) Experimental design. At 125 days post-B16-OVA challenge, tumor-surviving mice with prior antibody depletion regimens from Figure 1 or age-matched, immunized, tumor-naive mice were intravenously (IV) injected with a fluorophore-conjugated anti-CD45 antibody approximately 3 minutes before tissue harvest. Blood, spleen, cervical draining lymph nodes (cDLN), and brain tissues were isolated. (B) Representative flow plots and (C) frequencies of OT-I in the blood, spleen, cDLN, and IV– brain of tumor naive, tumor surviving isotype-treated mice, and tumor surviving a-Thy1.1-treated mice. (D) Number of OT-I in the IV– brain. (E) Representative histograms of TRM-associated markers among OT-I in tumor naive and antibody-treated tumor-surviving mice across tissue compartments. (F) Frequency of TRM-associated marker expression in isotype or a-Thy1.1 antibody-treated tumor-surviving mice. (G) Frequency of CD103+ IV– brain OT-I. (H) Frequency of IFN-γ+ OT-I in the IV– brain following 5–6-hour ex vivo 1 μM OVA257–264 peptide stimulation. Experiments (A–D) show concatenated data from 3 independent experiments with n = 6–11 mice per group total. Experiments (F and H) show representative data from 1 of 2 independent experiments with n = 4–6 mice per group. Experiments (G) show concatenated data from 2 independent experiments with n = 6–8 mice per group. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple comparison’s test. Graphs show the mean ± SEM with each symbol representing 1 mouse. Individual P values are noted on respective graphs or are otherwise summarized as: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Graphical illustrations were created using BioRender (https://biorender.com).