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 December 2, 2019; First 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

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 4

Endogenous lymphocytes prevent outgrowth of antigen-negative tumor cells.

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Endogenous lymphocytes prevent outgrowth of antigen-negative tumor cells...
NRG mice were inoculated i.d. with CMS5 cells 7 days prior to adoptive transfer of DUC18 Tcm (106 cells/mouse). One day after Tcm transfer, mice were vaccinated i.v. with VSV-ErkM (2 × 108 PFU/mouse). Mice receiving VSV-ErkM alone, Tcm alone, or PBS were included as controls. (A) Tumor volume and (B) survival of treated mice is shown at the indicated dpt. (C) The numbers of transferred (Thy1.1+) CD8+ T cells in the peripheral blood of TB and TF NRG mice on days 3, 5, 12, and 19 after combination therapy were determined by flow analysis. WT mice surviving initial CMS5 tumor challenge after treatment with Tcm plus VSV-ErkM were rechallenged with CMS5 relapse (CMS5r) cells 60 days later, and subsequent tumor growth (D) and survival (E) are shown. Naive mice that received CMS5 were included as controls. Data are shown as representative results of 3 (A and B) or 2 (C–E) independent experiments with n = 5 per group. Data were analyzed using repeated measures 2-way ANOVA with Holm-Šidák correction for multiple comparisons (C) and log-rank (Mantel-Cox) test (B and E). *P < 0.05; **P < 0.01. (F) Schematic of the PCR product resulting from genomic DNA amplification of the ERK2 gene is shown with the SfcI recognition sequence generated by the ErkM mutation displayed in uppercase letters. Expected fragments generated from SfcI digestion of PCR amplicons from WT ERK (356bp bands for ErKwt) and mutant ERK alleles (260 and 96 bp bands for ErKM) are shown with dotted brackets. (G) Restriction digestion of PCR products amplified from CT26 (negative control), CMS5, and CMS5r cell line genomic DNA is shown as well as (H) chromatogram of sequencing result from PCR products.