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Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth.

ABSTRACT: 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.

SUBMITTER: Das M

PROVIDER: S-EPMC7475277 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth.

Das Manisit M Zhou Xuefei X Liu Yun Y Das Anirban A Vincent Benjamin G BG Li Jingjing J Liu Rihe R Huang Leaf L

Translational oncology 20200828 12

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 neoanti ...[more]

PMID: 32862105

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Project description:BACKGROUND:The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor due to the difficulty of disease diagnosis and therapy. Immunotherapy has had robust performance against several malignancies, including PDAC. In this study, we aim to analyze the expression of CD8 and FoxP3 on T lymphocytes and TGF-? expression in tumor tissues, and then analyze the possible clinical significance of these finding in order to find a novel effective immunotherapy target in PDAC using a murine model. METHODS:A tissue microarray using patient PDAC samples was stained and analyzed for associations with clinicopathological characteristics. A preclinical murine model administrated with various immunotherapies were analyzed by growth inhibitor, flow cytometry, enzyme-linked immuno sorbent assay and immunohistochemistry. RESULTS:The infiltrating FoxP3+ regulatory T cells (Tregs) in tumor tissues were associated with survival, while CD8+ tumor infiltrating lymphocytes (TILs) were not. Considering the drawbacks of these measure alone, the number of CD8+ and FoxP3+ T cells were combined to create a new estimated value-integrated immune ratio (IIR), which showed excellent validity in survival risk stratification. IIR was further verified as an independent prognostic factor according to multivariate analysis as well as TGF-? expression. Association between TGF-? expression and infiltrating Tregs was also verified. Then, in our preclinical murine model, CD25 and TGF-? combination blockade had a higher tumor growth inhibitor value. This combination therapy significantly depleted periphery and intra-tumor FoxP3+ Tregs while increasing intra-tumor CD8+ TILs levels compared to controls or anti-TGF-? monotherapy (p?<?0.05). Anti-CD25 monotherapy alone also had the ability to deplete periphery and intra-tumor Tregs (p?<?0.05). The excretion of intra-tumor IL-10, TGF-? was notably lower but higher IFN-? excretion in this combination immunotherapy. Such combination immunotherapy was further confirmed to synergize with anti-PD-1 monotherapy to improve tumor growth inhibition and cure rates. CONCLUSIONS:The combination of CD25, TGF-? and PD-1 blockade plays a potentially effective role in inhibiting tumor formation and progression. Our results also provide a strong rational strategy for use of IIR in future immunotherapy clinical trials.

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Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth.

Publications

Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth.

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