Microfluidic Squeezing Enables MHC Class I Antigen Presentation by Diverse Immune Cells to Elicit CD8+ T Cell Responses with Antitumor Activity

Autor: Matthew G. Booty, Kelan A. Hlavaty, Adam Stockmann, Emrah Ilker Ozay, Carolyne Smith, Lina Tian, Edylle How, Disha Subramanya, Anita Venkitaraman, Christian Yee, Olivia Pryor, Kelly Volk, Katarina Blagovic, Ildefonso Vicente-Suarez, Defne Yarar, Melissa Myint, Amy Merino, Jonathan Chow, Tarek Abdeljawad, Harry An, Sophia Liu, Shirley Mao, Megan Heimann, LeeAnn Talarico, Miye K. Jacques, Eritza Chong, Lucas Pomerance, John T. Gonzalez, Ulrich H. von Andrian, Klavs F. Jensen, Robert Langer, Hendrik Knoetgen, Christine Trumpfheller, Pablo Umaña, Howard Bernstein, Armon Sharei, Scott M. Loughhead
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Immunology. 208:929-940
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.2100656
Popis: 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.
Databáze: OpenAIRE
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