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An effective mouse model for adoptive cancer immunotherapy targeting neoantigens
Ken-ichi Hanada, … , Adam S. Park, Nicholas P. Restifo
Ken-ichi Hanada, … , Adam S. Park, Nicholas P. Restifo
Published May 16, 2019
Citation Information: JCI Insight. 2019;4(10):e124405. https://doi.org/10.1172/jci.insight.124405.
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Resource and Technical Advance Immunology Vaccines

An effective mouse model for adoptive cancer immunotherapy targeting neoantigens

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Abstract

The adoptive cell transfer (ACT) of T cells targeting mutated neoantigens can cause objective responses in varieties of metastatic cancers, but the development of new T cell–based treatments relies on accurate animal models. To investigate the therapeutic effect of targeting a neoantigen with ACT, we used T cells from pmel-1 T cell receptor–transgenic mice, known to recognize a WT peptide, gp100, and a mutated version of the peptide that has higher avidity. We gene-engineered B16 cells to express the WT or mutated gp100 epitopes and found that pmel-1–specific T cells targeting a neoantigen tumor target augmented recognition as measured by IFN-γ production. Neoantigen expression by B16 also enhanced the capacity of pmel-1 T cells to trigger the complete and durable regression of large, established, vascularized tumor and required less lymphodepleting conditioning. Targeting neoantigen uncovered the possibility of using enforced expression of the IL-2Rα chain (CD25) in mutation-reactive CD8+ T cells to improve their antitumor functionality. These data reveal that targeting of “mutated-self” neoantigens may lead to improved efficacy and reduced toxicities of T cell–based cellular immunotherapies for patients with cancer.

Authors

Ken-ichi Hanada, Zhiya Yu, Gabrielle R. Chappell, Adam S. Park, Nicholas P. Restifo

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Figure 1

Modified B16 cell lines and their recognition by pmel-1 T cells.

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Modified B16 cell lines and their recognition by pmel-1 T cells.
(A) Sch...
(A) Schematic diagram. Retroviral vectors for genetic modifications: MSGV1 vectors containing cDNAs of (i) native mouse gp100, (ii) mouse gp100 modified at amino acid positions 25–27, or (iii) H-2Db were constructed. LTR, long-terminal repeat; EGS, Glu-Gly-Ser; KVP, Lys-Val-Pro; V5, V5 tag; IRES, internal ribosome entry site; BSR, blasticidin S resistance gene; PURO, puromycin resistance gene. (B) Western blot of cell lysates from modified B16 tumors probed by an anti-V5 tag antibody and an anti–β-actin antibody (loading control); #1 and #2 represent 2 retroviral plasmid preparations used for the transduction. (C) H-2Db expression analysis on modified B16, MC38, and MCA205 cells by flow cytometry. (D) ELISA measuring tumor recognition by pmel-1 T cells in coculture assay: 1 × 105 pmel-1 T cells were cocultured with the same number of tumor cells for 24 hours. IFN-γ concentration in the culture supernatant was measured by ELISA. The results represent 1 of 3 independent experiments. Error bars indicate the mean ± SD; n = 3. *P < 0.01 by ANOVA followed by Tukey’s multiple-comparisons test.

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