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 4

Brain TRM restrain tumor-associated peripheral immunosuppression and local neuroinflammation.

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Brain TRM restrain tumor-associated peripheral immunosuppression and loc...
(A) Experimental design. Naive or (OT-I) DC-rLM-OVA prime-boosted mice previously treated with low-dose a-Thy1.1 depleting antibody were challenged with B16-OVA or no tumor cells. At 21 days after B16-OVA challenge, blood, spleen, thymus, and brain tissues were isolated to determine immune profiles. (B) Number of CD4+ and (C) CD8+ T cells in the peripheral blood. (D) Splenic weight in grams (g). (E) Number of CD4+ and (F) CD8+ T cells in the spleen. (G) Thymic weight in grams (g). (H) Number of bulk thymocytes and (I) double negative (DN) thymocytes. (J) Proportion of DN1–4 staging among thymocytes according to CD44 and CD25 expression. (K) Frequency of TCR-β+ DN1 thymocytes. (L) Uniform manifold approximation and projection (UMAP) representations of 36,000 downsampled IV– brain CD45int-hi cells per group concatenated from n = 3 representative mice via flow cytometry. (M) Number of IV– CD45int-hi cells, (N) IV– infiltrating myeloid cells, (O) IV– CD4+ T cells, and (P) IV– endogenous (endo) CD8+ T cells. (Q) Representative histograms and (R) gMFI of PD-1 expression among endo CD8+ T cells or OT-I cells according to group. Experiments in (A–P) show concatenated data from 2 independent experiments with n = 5–10 mice per group total. Experiments (Q and R) show representative data from 1 independent experiment. 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. Graphical illustrations were created using BioRender (https://biorender.com).