The Tumor Immune Profile of Murine Ovarian Cancer Models: An Essential Tool For Ovarian Cancer Immunotherapy Research.
The Tumor Immune Profile of Murine Ovarian Cancer Models: An Essential Tool For Ovarian Cancer Immunotherapy Research.
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DOI：
10.1158/2767-9764.crc-22-0017
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
Vanderhyden BC
中科院分区：
文献类型：
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作者：
Rodriguez GM;Galpin KJC;Cook DP;Yakubovich E;Maranda V;Macdonald EA;Wilson-Sanchez J;Thomas AL;Burdette JE;Vanderhyden BC
上皮性卵巢癌（EOC）是最致命的妇科癌症，迫切需要新的治疗方法。免疫疗法在某些癌症类型中取得了显着的成功;然而，研究免疫检查点抑制剂治疗EOC疗效的临床试验使不到15%的患者受益。鉴于EOC从生殖系统的多个组织发展而来，并在整个腹膜腔广泛转移，因此对免疫治疗的反应可能会受到含有多种免疫特征的异质肿瘤微环境（TME）的阻碍。为了充分表征和比较可能反映这种多样性的同基因模型系统，我们通过单细胞RNA测序、流式细胞术和IHC确定了6种卵巢肿瘤模型的体内免疫原性、原位肿瘤的T细胞和髓系特征以及腹水的免疫组成和细胞因子特征。所选模型反映了EOC（卵巢和输卵管上皮）的不同细胞起源，并含有与人类疾病相关的突变，包括Tp 53突变、PTEN抑制和组成性KRAS激活。ID 8-p53−/−和ID 8-C3肿瘤被T细胞浸润最多，而STOSE和MOE-PTEN/KRAS肿瘤主要被肿瘤相关巨噬细胞浸润，并且在MHC I类和II类表达中是独特的。MOE-PTEN/KRAS肿瘤能够形成T细胞簇。这组定义明确的小鼠EOC模型反映了人类疾病中发现的一些异质性，可以作为旨在测试免疫疗法的研究的宝贵资源，探索对治疗的免疫应答机制，并指导患者群体的治疗选择。这项研究强调了在六种不同的原位卵巢癌模型中发现的免疫原性和免疫组成的主要差异，作为未来癌症免疫治疗临床前研究的重要工具。
Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC benefited less than 15% of patients. Given that EOC develops from multiple tissues in the reproductive system and metastasizes widely throughout the peritoneal cavity, responses to immunotherapy are likely hindered by heterogeneous tumor microenvironments (TME) containing a variety of immune profiles. To fully characterize and compare syngeneic model systems that may reflect this diversity, we determined the immunogenicity of six ovarian tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition and cytokine profile of ascites, by single-cell RNA sequencing, flow cytometry, and IHC. The selected models reflect the different cellular origins of EOC (ovarian and fallopian tube epithelium) and harbor mutations relevant to human disease, including Tp53 mutation, PTEN suppression, and constitutive KRAS activation. ID8-p53−/− and ID8-C3 tumors were most highly infiltrated by T cells, whereas STOSE and MOE-PTEN/KRAS tumors were primarily infiltrated by tumor-associated macrophages and were unique in MHC class I and II expression. MOE-PTEN/KRAS tumors were capable of forming T-cell clusters. This panel of well-defined murine EOC models reflects some of the heterogeneity found in human disease and can serve as a valuable resource for studies that aim to test immunotherapies, explore the mechanisms of immune response to therapy, and guide selection of treatments for patient populations. This study highlights the main differences in the immunogenicity and immune composition found in six different models of orthotopic ovarian cancer as an essential tool for future preclinical investigations of cancer immunotherapy.