Department of Bioengineering, Stanford University, Stanford, CA.
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA.
J Immunol. 2023 Jul 15;211(2):295-305. doi: 10.4049/jimmunol.2200950.
Spontaneous tumors that arise in genetically engineered mice recapitulate the natural tumor microenvironment and tumor-immune coevolution observed in human cancers, providing a more physiologically relevant preclinical model relative to implanted tumors. Similar to many cancer patients, oncogene-driven spontaneous tumors are often resistant to immunotherapy, and thus novel agents that can effectively promote antitumor immunity against these aggressive cancers show considerable promise for clinical translation, and their mechanistic assessment can broaden our understanding of tumor immunology. In this study, we performed extensive immune profiling experiments to investigate how tumor-targeted TLR9 stimulation remodels the microenvironment of spontaneously arising tumors during an effective antitumor immune response. To model the clinical scenario of multiple tumor sites, we used MMTV-PyMT transgenic mice, which spontaneously develop heterogeneous breast tumors throughout their 10 mammary glands. We found that i.v. administration of a tumor-targeting TLR9 agonist, referred to as PIP-CpG, induced a systemic T cell-mediated immune response that not only promoted regression of existing mammary tumors, but also elicited immune memory capable of delaying growth of independent newly arising tumors. Within the tumor microenvironment, PIP-CpG therapy initiated an inflammatory cascade that dramatically amplified chemokine and cytokine production, prompted robust infiltration and expansion of innate and adaptive immune cells, and led to diverse and unexpected changes in immune phenotypes. This study demonstrates that effective systemic treatment of an autochthonous multisite tumor model can be achieved using a tumor-targeted immunostimulant and provides immunological insights that will inform future therapeutic strategies.
自发肿瘤在基因工程小鼠中出现，重现了人类癌症中观察到的自然肿瘤微环境和肿瘤免疫共同进化，相对于植入肿瘤提供了更具生理相关性的临床前模型。与许多癌症患者一样，癌基因驱动的自发肿瘤通常对免疫疗法有抵抗力，因此，能够有效促进针对这些侵袭性癌症的抗肿瘤免疫的新型药物在临床转化方面显示出很大的前景，其机制评估可以拓宽我们对肿瘤免疫学的理解。在这项研究中，我们进行了广泛的免疫分析实验，以研究肿瘤靶向 TLR9 刺激如何在有效的抗肿瘤免疫反应过程中重塑自发发生的肿瘤的微环境。为了模拟多个肿瘤部位的临床情况，我们使用 MMTV-PyMT 转基因小鼠，这些小鼠在其 10 个乳腺中自发地发展出异质性乳腺癌。我们发现，静脉内给予肿瘤靶向 TLR9 激动剂，称为 PIP-CpG，可诱导全身性 T 细胞介导的免疫反应，不仅促进了现有乳腺肿瘤的消退，还引发了能够延迟独立新出现肿瘤生长的免疫记忆。在肿瘤微环境中，PIP-CpG 治疗引发了炎症级联反应，极大地放大了趋化因子和细胞因子的产生，促使先天和适应性免疫细胞的强烈浸润和扩张，并导致免疫表型的多样化和意外变化。这项研究表明，使用肿瘤靶向免疫刺激剂可以实现对同源多部位肿瘤模型的有效全身治疗，并提供了将为未来治疗策略提供信息的免疫学见解。
