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

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

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 5

Both endogenous CD4+ and CD8+ T cells are required to prevent tumor escape during combination therapy.

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Both endogenous CD4+ and CD8+ T cells are required to prevent tumor esca...
CMS5 TB BALB/c mice were depleted of specific lymphocyte populations via treatment with the indicated antibody or CPX concurrent with treatment with combination therapy, and resulting tumor growth (A) and survival (B) were monitored. Antibodies were given 1 day before and 1 day after T cell transfer and once a week thereafter for 3 weeks. A single injection of CPX was given 1 day before T cell transfer. (C) Frequency of antigen-spreading CD8+ T cell responses in the peripheral blood were quantified via stimulation with a pool of 4 peptides corresponding to previously identified CMS5 neoepitopes (27) and staining for IFN-γ production. (D) Frequency of ErkM-specific T cells in the peripheral blood of BALB/c mice surviving initial CMS5 tumor challenge after combination therapy (60+ days) was assessed before and 5 days after rechallenge with CMS5 or CM5 relapse (CMS5r) cells, and resultant survival (E) is also shown. Naive mice receiving the CMS5 or CMS5r challenge were included as controls. (F) Survival of mice vaccinated with lethally irradiated CMS5r cells (irrCMS5r) before challenge with CMS5 or CMS5r cells. (G) Survival of tumor-regressed mice (as described above) rechallenged with CMS5r after depletion of lymphocyte populations with the indicated antibodies. Data are shown as representative of 2 independent experiments (A–E and G) or a single experiment (F) with n = 5 per group. Data were analyzed using 1-way ANOVA with Holm-Šidák correction for multiple comparisons (C), paired 2-tailed t test (D), and log-rank (Mantel-Cox) test (B and E–G). *P < 0.05; **P < 0.01; ***P < 0.001.