Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth
The immunogenic clonal-fraction threshold in heterogeneous solid-tumor required to induce effective bystander-killing of non-immunogenic subclones is unknown. Pancreatic cancer poses crucial challenges for immune therapeutic interventions due to low mutational-burden and consequent lack of neoantige...
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doaj-8030f78e807b4cc39d063f5e83946b3e2020-11-25T03:41:08ZengElsevierTranslational Oncology1936-52332020-12-011312100856Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growthManisit Das0Xuefei Zhou1Yun Liu2Anirban Das3Benjamin G. Vincent4Jingjing Li5Rihe Liu6Leaf Huang7Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Computer Science, Rensselaer Polytechnic Institute, Troy, NY 12180, USALineberger Comprehensive Cancer Center, Department of Medicine, Division of Hematology/Oncology, Curriculum in Bioinformatics and Computational Biology, Computational Medicine Program, University of North Carolina, Chapel Hill, NC 27599-7295, USADivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USADivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author at: Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.The immunogenic clonal-fraction threshold in heterogeneous solid-tumor required to induce effective bystander-killing of non-immunogenic subclones is unknown. Pancreatic cancer poses crucial challenges for immune therapeutic interventions due to low mutational-burden and consequent lack of neoantigens. Here, we designed a model to incorporate artificial-neoantigens into genes-of -interest in cancer-cells and to test their potential to actuate bystander-killing. By precisely controlling a neoantigen's abundance in the tumor, we studied the impact of neoantigen frequency on immune-response and immune-escape. Our results showed single, strong, widely-expressed neoantigen could lead to robust antitumor response when over 80% of cancer cells express the neoantigen. Further, immunological assays demonstrated T-cell responses against non-target self-antigen on KRAS-oncoprotein, when we inoculated animals with a high frequency of tumor-cells expressing test-neoantigen. Using nanoparticle-based gene-therapy, we successfully altered tumor-microenvironment by perturbing interleukin-12 and interleukin-10 gene-expression. The subsequent microenvironment-remodeling reduced the neoantigen frequency threshold at which bioluminescent signal intensity for tumor-burden decreased 1.5-log-fold, marking robust tumor-growth inhibition, from 83% to 29%. Our results thus suggest bystander killing is inefficient in immunologically-cold tumors like pancreatic-cancer and requires high neoantigen abundance. However, bystander killing mediated antitumor response can be rescued by adjuvant-immune therapy.http://www.sciencedirect.com/science/article/pii/S193652332030348X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Manisit Das Xuefei Zhou Yun Liu Anirban Das Benjamin G. Vincent Jingjing Li Rihe Liu Leaf Huang |
spellingShingle |
Manisit Das Xuefei Zhou Yun Liu Anirban Das Benjamin G. Vincent Jingjing Li Rihe Liu Leaf Huang Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth Translational Oncology |
author_facet |
Manisit Das Xuefei Zhou Yun Liu Anirban Das Benjamin G. Vincent Jingjing Li Rihe Liu Leaf Huang |
author_sort |
Manisit Das |
title |
Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth |
title_short |
Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth |
title_full |
Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth |
title_fullStr |
Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth |
title_full_unstemmed |
Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth |
title_sort |
tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth |
publisher |
Elsevier |
series |
Translational Oncology |
issn |
1936-5233 |
publishDate |
2020-12-01 |
description |
The immunogenic clonal-fraction threshold in heterogeneous solid-tumor required to induce effective bystander-killing of non-immunogenic subclones is unknown. Pancreatic cancer poses crucial challenges for immune therapeutic interventions due to low mutational-burden and consequent lack of neoantigens. Here, we designed a model to incorporate artificial-neoantigens into genes-of -interest in cancer-cells and to test their potential to actuate bystander-killing. By precisely controlling a neoantigen's abundance in the tumor, we studied the impact of neoantigen frequency on immune-response and immune-escape. Our results showed single, strong, widely-expressed neoantigen could lead to robust antitumor response when over 80% of cancer cells express the neoantigen. Further, immunological assays demonstrated T-cell responses against non-target self-antigen on KRAS-oncoprotein, when we inoculated animals with a high frequency of tumor-cells expressing test-neoantigen. Using nanoparticle-based gene-therapy, we successfully altered tumor-microenvironment by perturbing interleukin-12 and interleukin-10 gene-expression. The subsequent microenvironment-remodeling reduced the neoantigen frequency threshold at which bioluminescent signal intensity for tumor-burden decreased 1.5-log-fold, marking robust tumor-growth inhibition, from 83% to 29%. Our results thus suggest bystander killing is inefficient in immunologically-cold tumors like pancreatic-cancer and requires high neoantigen abundance. However, bystander killing mediated antitumor response can be rescued by adjuvant-immune therapy. |
url |
http://www.sciencedirect.com/science/article/pii/S193652332030348X |
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