CAR-NKT cells target tumor cells in vitro. ARepresentative flow cytometry graphs illustrating the purity of NKT cells isolated from the spleen of iVα14-Jα18 transgenic mice, n= 12 with similar results. b,cRepresentative flow cytometry histograms (b) and summary data (c) illustrating the expression of CAR.CD19 in NKT cells and T cells; n = 4 mice; Ordinary one-way ANOVA. dIn vitro expansion of CAR-NKT cells and CAR-T cells; n= 3 mice; P. ≥ 0.05 per unpaired bilateral multiple t-test. e–gRepresentative flow cytometry curves (e) and summary results (f And g) showing coculture of CAR-NKT or CAR-T cells with B16-OVA-hCD19 tumor cells. T cells and NKT cells were co-cultured with tumor cells at an E:T ratio of 1:1 for 5 days. On day 5, all cells were collected and analyzed by flow cytometry to quantify tumor cells (hCD19+) (f) and T/NKT cells (CD3+) (g), respectively; n= 4 mice, ordinary one-way ANOVA. (h And I) IFN-γ (h) and IL-2 (I) detection in the coculture supernatants (24 h) of the coculture experiments described in e; n= 4 mice; Ordinary one-way ANOVA. In this figure, data are presented as mean ± standard deviation. Credit : Natural cancer(2024). DOI: 10.1038/s43018-024-00830-0
In the fight against cancer, chimeric antigen receptor T cell (CAR-T) therapy has achieved notable success in the treatment of blood cancers. However, it has been found to be largely ineffective against solid tumors.
Now, a newly published study by researchers at the UNC Lineberger Comprehensive Cancer Center demonstrates that a different immunotherapy approach using natural killer T (NKT) cells produced significant antitumor activity in preclinical tumor models. solid.
Gianpietro Dotti, MD, professor of microbiology and immunology at the UNC School of Medicine and co-leader of the UNC Lineberger Immunology Research Program, Xin Zhou, Ph.D., postdoctoral researcher in the laboratory Dotti, and colleagues report that CAR-Natural Killer T (CAR-NKT) cells use a multimodal approach, combining direct killing of tumor cells, reprogramming of the tumor microenvironment, and promotion of systemic immune responses, to create a more immunogenic in tumors.
Their findings are published in Natural Cancer.
“CAR-T cells are very potent cells. However, the most surprising finding of our work is that these potent cells are strongly inhibited in tumor models that recapitulate the complexity of the tumor microenvironment,” said Dotti, the corresponding author of the article. “In particular, tumor-associated macrophages appear to have a potent inhibitory effect on CAR-T cells. CAR-NKTs appear able to avoid the inhibitory effects of macrophages since they can target them directly.”
Previous research has shown that the limited ability of CAR-T cells to enter and function in solid tumors is primarily due to physical barriers within tumors and the suppressive nature of the tumor microenvironment. Natural killer T cells have innate properties that make them uniquely equipped to fight solid tumors. Specifically, they express a T cell receptor that recognizes glycolipid antigens presented by CD1d molecules.
Dotti, Zhou, and colleagues demonstrated that CAR-NKT cells effectively eliminated CD1d-expressing M2-like macrophages in the tumor microenvironment. These macrophages promote tumor growth and suppress immune responses, making their elimination an essential aspect of enhancing antitumor immunity. By targeting these cells, CAR-NKT therapy effectively reprograms the tumor microenvironment from a pro-tumor environment to an anti-tumor environment.
They also reported that CAR-NKT cells promoted epitope spreading – a process by which the immune system recognizes and attacks new targets – leading to activation of T cell responses.
“Our results demonstrate that CAR-NKT cells not only effectively eliminate CD1d-expressing M2-like macrophages in the tumor microenvironment, but also stimulate endogenous immune cells,” said Zhou, first author of the paper. “This dual function, defeating suppressive immune cells and promoting sustained immune activity, represents a crucial advance in improving CAR-based therapies for solid tumors and achieving long-term tumor control.”
The researchers also report that they were able to help CAR-NKT cells overcome therapeutic exhaustion, a known defect of CAR-T therapies that have undergone prolonged exposure to tumor antigens. Signs of exhaustion include co-expression of the immune checkpoint markers PD1 and TIM3, which attenuate the effectiveness of immune cells. However, the researchers demonstrated that combining CAR-NKT cells with PD1 blockade – an immune checkpoint inhibitor commonly used in cancer treatment – significantly increased their anti-tumor activity.
Researchers also reported that combining CAR-NKT cells with vaccination approaches, such as those using alpha-galactosylceramide-loaded dendritic cells, further enhanced the antitumor response. Alpha-galactosylceramide is a known potent stimulator of NKT cells.
Looking ahead, Dotti said his team is focused on developing approaches to simplify the process of producing CAR-NKT cells. “CAR-NKT cells have already been used safely in clinical trials. However, manufacturing CAR-NKT for clinical purposes is more complex than manufacturing CAR-T cells. We are working to simplify the manufacturing of CAR-NKT.
More information:
Xin Zhou et al, CAR-redirected natural killer T cells demonstrate superior antitumor activity than CAR-T cells through CD1d-dependent multimodal mechanisms, Natural Cancer(2024). DOI: 10.1038/s43018-024-00830-0
Provided by University of North Carolina Health Care
Quote: Harnessing natural killer T cells to advance cancer immunotherapy for solid tumors (October 7, 2024) retrieved October 7, 2024 from
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