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

Cellular & Molecular Immunology volume 21, pages 91–94 (2024)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.

Taken together our findings demonstrate that CAFs express CD1d as well as the costimulatory molecule CD80 and that this expression is driven by the TME. Also, the in vitro experiments show that CD1d expressed by CAFs can present self-lipids under conditions of cellular stress to NKT cells. This could occur during different stages of tumor growth related to hypoxia or when patients go through treatments that induce local cell death including chemotherapy or immunotherapy. Further studies are needed to investigate if this would contribute to treatment efficacy or if local regulation imposed by CAF-activated iNKT cells would work against the treatment. Also, it will be of interest to examine other cancer types and the value of using presence of CD1-expressing CAFs to determine treatment outcomes. Recently many studies have used high throughput technologies to dissect CAF heterogeneity and found several distinct subpopulations. Of note is that one of these populations have been found to also express MHC class II molecules and these have been found in both pancreatic and lung cancer [11]. In the study investigating CAFs from pancreatic tumors it was shown that the interaction with CD4 positive T cells was driving expansion of regulatory T cells. This could be potentially further enhanced by iNKT cells as it has been shown that they can enhance and influence regulatory T cell function at least in response to foreign ligands [12]. On the other hand, regulatory T cells can also induce iNKT cell anergy and stop their capacity to kill tumor cells. Finally, it will be of importance to evaluate how cellular stress responses modulate clinical outcomes of treatment and here we now show a direct link between stromal cells and unconventional T cells that could be employed.

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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 21, 91–94 (2024). https://doi.org/10.1038/s41423-023-01082-1

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