Optogenetically engineered Septin-7 enhances immune cell infiltration of tumor spheroids

• 成果类型: Article
• 署名作者: Chen, Jiaxing; Hnath, Brianna; Sha, Congzhou M.; Beidler, Lynne; Schell, Todd D.; Dokholyan, Nikolay V.
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12764
• DOI: 10.1073/pnas.2405717121
• 发表日期: 2024-10-29
• 关键词: discrete molecular-dynamics; t-cells; evolutionary conservation; immunotherapy; allostery; disease; antigen

摘要

Chimeric antigen receptor T cell therapies have achieved great success in eradicating some liquid tumors, whereas the preclinical results in treating solid tumors have proven less decisive. One of the principal challenges in solid tumor treatment is the physical barrier composed of a dense extracellular matrix, which prevents immune cells from penetrating the tissue to attack intratumoral cancer cells. Here, we improve immune cell infiltration into solid tumors by manipulating septin-7 functions in cells. Using protein allosteric design, we reprogram the three- dimensional structure of septin-7 and insert a blue light- responsive light- oxygen- voltage- sensing domain 2 (LOV2), creating a light- controllable septin- 7-LOV2 hybrid protein. Blue light inhibits septin-7 function in live cells, inducing extended cell protrusions and cell polarization, enhancing cell transmigration efficiency through confining spaces. We genetically edited human natural killer cell line (NK92) and mouse primary CD8+T-cells expressing the engineered protein, and we demonstrated improved penetration and cytotoxicity against various tumor spheroid models. Our proposed strategy to enhance immune cell infiltration is compatible with other methodologies and therefore, could be used in combination to further improve cell- based immunotherapies against solid tumors.