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Lack of immunoediting in murine pancreatic cancer reversed with neoantigen
Rebecca A. Evans, … , Rafael Winograd, Robert H. Vonderheide
Rebecca A. Evans, … , Rafael Winograd, Robert H. Vonderheide
Published September 8, 2016
Citation Information: JCI Insight. 2016;1(14):e88328. https://doi.org/10.1172/jci.insight.88328.
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Research Article Immunology Oncology

Lack of immunoediting in murine pancreatic cancer reversed with neoantigen

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Abstract

In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through “immunoediting,” whereby tumors adapt to immune pressure and escape T cell–mediated killing. Many tumors lack a high neoepitope burden, and it remains unclear whether immunoediting occurs in such cases. Here, we evaluated T cell immunity in an autochthonous mouse model of pancreatic cancer and found a low mutational burden, absence of predicted neoepitopes derived from tumor mutations, and resistance to checkpoint immunotherapy. Spontaneous tumor progression was identical in the presence or absence of T cells. Moreover, tumors arising in T cell–depleted mice grew unchecked in immune-competent hosts. However, introduction of the neoantigen ovalbumin (OVA) led to tumor rejection and T cell memory, but this did not occur in OVA immune-tolerant mice. Thus, immunoediting does not occur in this mouse model — a likely consequence, not a cause, of absent neoepitopes. Because many human tumors also have a low missense mutational load and minimal neoepitope burden, our findings have clinical implications for the design of immunotherapy for patients with such tumors.

Authors

Rebecca A. Evans, Mark S. Diamond, Andrew J. Rech, Timothy Chao, Max W. Richardson, Jeffrey H. Lin, David L. Bajor, Katelyn T. Byrne, Ben Z. Stanger, James L. Riley, Nune Markosyan, Rafael Winograd, Robert H. Vonderheide

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Figure 5

Immunity is dependent on cytotoxic Ova-specific CD8 T cells.

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Immunity is dependent on cytotoxic Ova-specific CD8 T cells.
(A) From th...
(A) From the experimental schema in Figure 4A, Ova-specific CD8+ T cells in 80% V6.OVA tumors at day 14 were compared with spleens and quantified in the tumor in all cohorts. n = 5–7 mice per cohort; data are representative of 3 independent experiments. ***P < 0.001 by unpaired 2-tailed Student’s t test. ****P < 0.0001 by 2-way ANOVA. Data are shown as whisker plots (symbols represent individual experimental measurements; center line, mean; outer lines; 1 SD). (B) Intratumoral CD8+ T cells in 80% V6.Ova-implanted mice were assessed by flow cytometry for intracellular levels of granzyme B and Tbet at day 21. Ki67 and IFN-γ expression was also assessed with or without stimulation with PMA/ionomycin. n = 6 mice per cohort. Data are representative of 2 independent experiments. ***P < 0.001 by unpaired 2-tailed Student’s t test. ****P < 0.0001 by 2-way ANOVA. (C) Tumor-enriched live cells (CD45–CD31–CD90–) were assessed for Td-Tomato expression by flow cytometry; Td-tomato+ cells are shown as a percentage of this tumor-enriched population across cohorts. n = 5–7 mice per cohort. Data are representative of 3 independent experiments. ****P < 0.0001 calculated by 2-way ANOVA. Representative data are shown as a histogram of Td-tomato expression for each cohort. (D) H&E stain of an isotype-treated 80% V6.Ova tumor (original magnification, ×10).

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