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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 1

T cell dependency of KPC pancreatic cancer.

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T cell dependency of KPC pancreatic cancer.
(A) Experimental design for ...
(A) Experimental design for survival studies of syngeneic KPC mice treated with an isotype control antibody, depleted of CD4 and CD8 T cells (αCD4/αCD8), or depleted of CD8 T cells alone (αCD8) beginning at 3–5 weeks of age. n = 19–21 mice per cohort. Starting at 7–8 weeks of age, mice were monitored by ultrasound every other week for tumor development and examined daily for morbidity. (B) Representative image of a tumor at the time of diagnosis by abdominal ultrasound (volume = 19 mm3). IVC, inferior vena cava. (C) Tumor-free survival according to ultrasound monitoring (time to diagnosis) and overall survival according to daily monitoring for the 3 cohorts described in A. P values were determined by log-rank (Mantel-Cox) analysis. (D) H&E staining of a representative pancreatic tumor from each treatment cohort (original magnification, ×10). (E) Flow cytometric analysis of tumors at the time of euthanasia (4–6 mice per cohort) to assess infiltration by leukocytes (CD45+ cells as percentage of viable cells), macrophages (CD45+CD19–F4/80+ as percentage of viable CD45+ cells), and immature myeloid cells (CD45+CD19–Gr-1+CD11b+ as percentage of viable CD45+ cells). Data are shown as whisker plots (symbols represent individual experimental measurements; center line, mean; outer lines; 1 SD), with P values determined by 2-way ANOVA.

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ISSN 2379-3708

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