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Cancer-associated fibroblasts express CD1d and activate invariant natural killer T cells under cellular stress

Cellular & Molecular Immunology (2023)Cite this article

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Invariant natural killer T (iNKT) cells are part of the family of unconventional T cells, and they recognize glycolipid antigens presented on the MHC class I like molecule CD1 [1]. In humans there are five CD1 molecules named CD1a to CD1e, whereas mice use only CD1d for lipid presentation. Functionally, iNKT cells can elicit both cytotoxicity similarly to conventional CD8 T cells and secrete cytokines that influence the adaptive immune response including providing direct T cell help to B cells [2]. In the context of tumors, they can use both release of granzyme B and use Fas-mediated mechanisms for killing of tumor cells. As iNKT cells use a restricted TCR repertoire and CD1 molecules are non-heterogenous the risk of graft vs host disease is limited and thus these T cells have been an attractive option for off the shelf immunotherapy to treat cancer [3]. So far clinical trials have mostly focused on using the glycolipid alpha-Galactosyl Ceramide (αGalCer) to activate iNKT cells and the outcomes have been varied [3]. Thus, to make immunotherapy using iNKT cells more efficient additional information is needed on how these T cells are activated and operate in the complex tumor microenvironment (TME). In mice CD1d is mainly found on antigen presenting cells (APC) including dendritic cells (DC), macrophages and B cells. These cells interact with iNKT cells in secondary lymphoid organs to activate them and polarize them to different effector functions. Besides activation by exogenous ligands like αGalCer, iNKT cell can also be activated by endogenous glycolipids that are induced by cellular stress and presented by CD1d as shown by using myeloid cells as APCs [4]. In the context of the TME little is known regarding which cell types that express CD1d and to what extent local regulation of iNKT cells occur. Also, it is not known if the presentation here is related to cellular stress or if endogenous ligands can be used and presented to pave way for more efficient iNKT cell mediated immunotherapy.

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Acknowledgements

We would like to thank Prof. Arne Östman and Dr. Marit Melssen for critical input to this manuscript. The work was supported by the Swedish Research council and the Swedish cancer foundation.

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Authors and Affiliations

  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    Shengduo Pei, Yueyun Pan & Mikael C. I. Karlsson

  2. Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden

    Jonas Sjölund & Kristian Pietras

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  1. Shengduo Pei
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Contributions

MCIK and SP conceived the original idea, designed the project and wrote the manuscript with input and revisions by YP, JS and KP. YP and SP performed animal and in vitro experiments. JS performed data analysis and bioinformatics.

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Correspondence to Mikael C. I. Karlsson.

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Pei, S., Sjölund, J., Pan, Y. et al. Cancer-associated fibroblasts express CD1d and activate invariant natural killer T cells under cellular stress. Cell Mol Immunol (2023). https://doi.org/10.1038/s41423-023-01082-1

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