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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 4

Selective outgrowth of Ova– tumors in immune-competent mice.

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Selective outgrowth of Ova– tumors in immune-competent mice.
(A) Experim...
(A) Experimental design of a competition assay between V6.Ova cells and negatively sorted (OvaNeg) cells subcutaneously implanted at the following ratios in immune-competent or CD8-depleted cohorts (n = 5 mice per cohort): 100% V6.Ova (7.5 × 105 V6.Ova cells); 90% V6.Ova/10%OvaNeg (6.75 × 105 V6.Ova cells and 0.75 × 105 OvaNeg cells); 80% V6.Ova/20%OvaNeg (6.0 × 105 V6.Ova cells and 1.5 × 105 OvaNeg cells); and 100%OvaNeg (7.5 × 105 OvaNeg cells). (B) Implants containing either a combination of Ova+ and Ova– cells (90% V6.Ova and 80% V6.Ova) or a 100% population of V6.Ova or OvaNeg cells were assessed for tumor growth. Data are shown as the individual growth curves for each mouse per cohort (n = 5 mice per cohort). Three independent experiments were performed. P values represent 2-way ANOVA. Overall survival was assessed by log-rank (Mantel-Cox) for each cohort.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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