1. Microfluidic Squeezing Enables MHC Class I Antigen Presentation by Diverse Immune Cells to Elicit CD8 + T Cell Responses with Antitumor Activity.
- Author
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Booty MG, Hlavaty KA, Stockmann A, Ozay EI, Smith C, Tian L, How E, Subramanya D, Venkitaraman A, Yee C, Pryor O, Volk K, Blagovic K, Vicente-Suarez I, Yarar D, Myint M, Merino A, Chow J, Abdeljawad T, An H, Liu S, Mao S, Heimann M, Talarico L, Jacques MK, Chong E, Pomerance L, Gonzalez JT, von Andrian UH, Jensen KF, Langer R, Knoetgen H, Trumpfheller C, Umaña P, Bernstein H, Sharei A, and Loughhead SM
- Subjects
- Adoptive Transfer, Animals, Antigen-Presenting Cells metabolism, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes metabolism, Cell Culture Techniques, Female, Humans, Immunization, Immunophenotyping, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Mice, Mice, Knockout, Models, Biological, Neoplasms metabolism, Neoplasms pathology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Antigen Presentation, Antigen-Presenting Cells immunology, CD8-Positive T-Lymphocytes immunology, Histocompatibility Antigens Class I immunology, Microfluidics methods, Neoplasms immunology
- Abstract
CD8
+ T cell responses are the foundation of the recent clinical success of immunotherapy in oncologic indications. Although checkpoint inhibitors have enhanced the activity of existing CD8+ T cell responses, therapeutic approaches to generate Ag-specific CD8+ T cell responses have had limited success. Here, we demonstrate that cytosolic delivery of Ag through microfluidic squeezing enables MHC class I presentation to CD8+ T cells by diverse cell types. In murine dendritic cells (DCs), squeezed DCs were ∼1000-fold more potent at eliciting CD8+ T cell responses than DCs cross-presenting the same amount of protein Ag. The approach also enabled engineering of less conventional APCs, such as T cells, for effective priming of CD8+ T cells in vitro and in vivo. Mixtures of immune cells, such as murine splenocytes, also elicited CD8+ T cell responses in vivo when squeezed with Ag. We demonstrate that squeezing enables effective MHC class I presentation by human DCs, T cells, B cells, and PBMCs and that, in clinical scale formats, the system can squeeze up to 2 billion cells per minute. Using the human papillomavirus 16 (HPV16) murine model, TC-1, we demonstrate that squeezed B cells, T cells, and unfractionated splenocytes elicit antitumor immunity and correlate with an influx of HPV-specific CD8+ T cells such that >80% of CD8s in the tumor were HPV specific. Together, these findings demonstrate the potential of cytosolic Ag delivery to drive robust CD8+ T cell responses and illustrate the potential for an autologous cell-based vaccine with minimal turnaround time for patients., (Copyright © 2022 by The American Association of Immunologists, Inc.)- Published
- 2022
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