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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 2

KPC-derived tumor cell lines grow progressively upon implantation, regardless of donor or host T cell status.

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KPC-derived tumor cell lines grow progressively upon implantation, regar...
(A) Experimental design using syngeneic pancreatic ductal adenocarcinoma (PDA) cell lines generated from immune-competent KPC mice or KPC mice serially depleted of CD4/CD8 T cells beginning at 3–5 weeks of age, as shown in Figure 1A. Cell lines were implanted subcutaneously (S.C.) in syngeneic mice predepleted of CD4 and CD8 T cells or administered an isotype control antibody (n = 8–10 mice per cohort). Tumor growth was measured by caliper over time, and mice were monitored for overall survival. (B) Subcutaneous tumor growth of 4662 PDA cells in immune-competent syngeneic hosts (Isotype control) or immune-compromised mice (αCD4/αCD8), shown with high inoculum (5 × 105 tumor cells) or low inoculum (105 cells). For the lower dose, mice were also monitored for overall survival. Growth data are shown as spaghetti plots of individual mice, and P values indicate analysis by 2-way ANOVA. Survival data were analyzed by log-rank (Mantel-Cox) test. (C) Histology of 4662 implanted tumor after 3 weeks of growth (left panels) stained by H&E and Masson’s trichrome. Right panels show H&E and trichrome staining of an autochthonous KPC tumor. Original magnification, ×10. (D) Subcutaneous growth of CD4- and CD8-depleted KPC cell lines (1262, 1493, and 1638; generated as described in A) in immune-competent syngeneic isotype control or αCD4/αCD8 mice. n = 8–10 mice per cohort. P values shown were generated by 2-way ANOVA. (E) Numbers of predicted neoepitopes for the B16 murine melanoma cell line, the 4662 PDA cell line derived from an immune-competent KPC mouse, and 3 cell lines derived from T cell–depleted KPC mice (1262, 1493, and 1638). Predictions are shown for both the 50 nM binding threshold (black bars) and 100 nM threshold (gray bars).

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