Priming of naive T cells inside tumors leads to eradication of established tumors

Abstract

The tumor barrier comprised of nonantigenic stromal cells may contribute to the failure of tumor rejection. The tumor-necrosis factor superfamily member LIGHT (also known as TNFSF-14) is a ligand of stromal cell–expressed lymphotoxin-β receptor and T cell–expressed herpes viral entry mediator (HVEM). Here we show that forced expression of LIGHT in the tumor environment induces a massive infiltration of naive T lymphocytes that correlates with an upregulation of both chemokine production and expression of adhesion molecules. Activation of these infiltrating T cells, possibly through HVEM, leads to the rejection of established, highly progressive tumors at local and distal sites. Our study indicates that targeting the tumor barrier may be an effective strategy for cancer immunotherapy.

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Figure 1: Growth kinetics of LIGHT-expressing Ag104Ld and parental tumors in C3B6F1 and B6-Rag1−/− mice.
Figure 2: Increased infiltration of CD8+ T cells in LIGHT-expressing Ag104Ld tumor tissues.
Figure 3: The modified extracellular domain of LIGHT is sufficient to costimulate purified T cell responses.
Figure 4: Increased LTβR-regulated chemokines and adhesion molecules in Ag104Ld-LIGHT tumors.
Figure 5: LIGHT-mediated Ag104Ld tumor environment recruits and activates naive 2C T cells leading to tumor rejection.
Figure 6: Injection of LIGHT-expressing Ag104Ld cells leads to eradication of established parental tumors and B16-OVA tumors.

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Acknowledgements

We thank L. Chen for advice and support, and M. Spiotto and J. Lo for their technical assistance. This work was supported by grants from the NIH (R01-HD37104, R01-DK58897 and P01-CA09296-01). P.Y. is a recipient of an NIH training grant (5T32DK07074).

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Correspondence to Yang-Xin Fu.

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Yu, P., Lee, Y., Liu, W. et al. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol 5, 141–149 (2004). https://doi.org/10.1038/ni1029

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