MYC 癌基因与肿瘤免疫抑制有关，靶向 Myc 可诱导肿瘤细胞免疫原性，用于治疗性全细胞疫苗接种。

MYC oncogene is associated with suppression of tumor immunity and targeting Myc induces tumor cell immunogenicity for therapeutic whole cell vaccination.

机构信息

The Sheikh Zayed Institute for Pediatric Surgical Innovation, Childrens Hospital Medical Center, Washington, District of Columbia, USA.

Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA.

出版信息

J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-001388.

DOI:10.1136/jitc-2020-001388

PMID:33757986

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7993333/

Abstract

BACKGROUND

MYC oncogene is deregulated in 70% of all human cancers and is associated with multiple oncogenic functions including immunosuppression in the tumor microenvironment. The role of MYC in the immune microenvironment of neuroblastoma and melanoma is investigated and the effect of targeting Myc on immunogenicity of cancer cells is evaluated.

METHODS

Immune cell infiltrates and immunogenic pathway signatures in the context of MYCN amplification were analyzed in human neuroblastoma tumors and in metastatic melanoma. Dose response and cell susceptibility to MYC inhibitors (I-BET726 and JQ1) were determined in mouse cell lines. The influence of downregulating Myc in tumor cells was characterized by immunogenic pathway signatures and functional assays. Myc-suppressed tumor cells were used as whole cell vaccines in preclinical neuroblastoma and melanoma models.

RESULTS

Analysis of immune phenotype in human neuroblastoma and melanoma tumors revealed that MYCN or c-MYC amplified tumors respectively are associated with suppressed immune cell infiltrates and functional pathways. Targeting Myc in cancer cells with I-BET726 and JQ1 results in cell cycle arrest and induces cell immunogenicity. Combining vaccination of Myc-inhibited tumor cells with checkpoint inhibition induced robust antitumor immunity and resulted in therapeutic cancer vaccine therapy in mouse neuroblastoma tumors. Despite vigorous antitumor immunity in the mouse melanoma model, upregulation of immunosuppressive pathways enabled tumor escape.

CONCLUSIONS

This study demonstrates that the Myc oncogene is an appropriate target for inducing tumor cell immunogenicity and suggests that Myc-suppressed whole tumor cells combined with checkpoint therapy could be used for formulating a personalized therapeutic tumor vaccine.

摘要

背景

MYC 癌基因在所有人类癌症中约有 70%存在失调，与包括肿瘤微环境中的免疫抑制在内的多种致癌功能有关。本研究调查了 MYC 在神经母细胞瘤和黑色素瘤免疫微环境中的作用，并评估了针对 Myc 对癌细胞免疫原性的影响。

方法

分析了人类神经母细胞瘤肿瘤和转移性黑色素瘤中 MYCN 扩增背景下的免疫细胞浸润和免疫原性途径特征。在小鼠细胞系中确定了 MYC 抑制剂（I-BET726 和 JQ1）的剂量反应和细胞敏感性。通过免疫原性途径特征和功能测定来描述下调肿瘤细胞中 Myc 的影响。将 Myc 下调的肿瘤细胞用作神经母细胞瘤和黑色素瘤临床前模型中的全细胞疫苗。

结果

对人类神经母细胞瘤和黑色素瘤肿瘤的免疫表型分析表明，MYCN 或 c-MYC 扩增的肿瘤分别与抑制性免疫细胞浸润和功能途径相关。用 I-BET726 和 JQ1 靶向癌细胞中的 Myc 会导致细胞周期停滞并诱导细胞免疫原性。用 Myc 抑制的肿瘤细胞进行疫苗接种与检查点抑制相结合，在小鼠神经母细胞瘤肿瘤中引发了强大的抗肿瘤免疫，并导致了治疗性癌症疫苗治疗。尽管在小鼠黑色素瘤模型中存在强烈的抗肿瘤免疫，但免疫抑制途径的上调使肿瘤得以逃避。