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Endogenous T cells prevent tumor immune escape following adoptive T cell therapy
Scott R. Walsh, … , Brian D. Lichty, Yonghong Wan
Scott R. Walsh, … , Brian D. Lichty, Yonghong Wan
Published November 4, 2019
Citation Information: J Clin Invest. 2019;129(12):5400-5410. https://doi.org/10.1172/JCI126199.
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Research Article Therapeutics Vaccines

Endogenous T cells prevent tumor immune escape following adoptive T cell therapy

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Abstract

While the outcome of adoptive T cell therapy (ACT) is typically correlated with the functionality of the inoculated T cells, the role of the endogenous T cells is unknown. The success of checkpoint blockade therapy has demonstrated the potentially curative value of preexisting tumor-primed T cells in cancer treatment. Given the results from checkpoint blockade therapy, we hypothesized that endogenous T cells contribute to long-term survival following ACT. Here, we describe a therapeutic approach combining ACT with an oncolytic vaccine that allows simultaneous analysis of antitumor immunity mediated by transferred and endogenous T cells. We found that, in addition to promoting the expansion and tumor infiltration of the transferred T cells, oncolytic vaccines boosted tumor-primed host T cells. We determined that transferred T cells contributed to rapid destruction of large tumor masses while endogenous T cells concurrently prevented the emergence of antigen-loss variants. Moreover, while transferred T cells disappeared shortly after tumor regression, endogenous T cells secured long-term memory with a broad repertoire of antigen specificity. Our findings suggest that this combination strategy may exploit the full potential of ACT and tumor-primed host T cells to eliminate the primary tumor, prevent immune escape, and provide long-term protective memory.

Authors

Scott R. Walsh, Boris Simovic, Lan Chen, Donald Bastin, Andrew Nguyen, Kyle Stephenson, Talveer S. Mandur, Jonathan L. Bramson, Brian D. Lichty, Yonghong Wan

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Figure 2

OVV treatment drives tumor core infiltration of transferred CD8+ T cells.

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OVV treatment drives tumor core infiltration of transferred CD8+ T cells...
Micrographs of CMS5 tumor tissues stained with an anti-CD8 antibody show relative infiltration of the tumor core and periphery with T cells induced by the indicated treatments. Low-magnification images of the whole tumor are shown in left panels, and higher magnification images of the tumor periphery (outlined by black boxes) and tumor core (outlined by blue boxes) are shown in the center and right panels. Scale bars: 500 μm (left panels); 200 μm (center and right panels).
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