Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, 33612, USA.
Radiat Oncol. 2024 Sep 13;19(1):121. doi: 10.1186/s13014-024-02514-6.
Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well-infiltrated, immunologically inflamed tumor beds, or immune deserts with low levels of infiltration. The pre-treatment immune make-up of the TIME is associated with treatment outcome; immunologically inflamed tumors generally exhibit better responses to radio- and immunotherapy than non-inflamed tumors. However, radiotherapy is known to induce opposing immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks (SFRT-GRID) or lattice radiotherapy to create areas of low or high dose exposure, may create protective reservoirs of the tumor immune microenvironment, thereby preserving anti-tumor immune responses that are pivotal for radiation success.
We have developed an agent-based model (ABM) of tumor-immune interactions to investigate the immunological consequences and clinical outcomes after whole tumor radiation therapy (WTRT) and SFRT-GRID. The ABM is conceptually calibrated such that untreated tumors escape immune surveillance and grow to clinical detection. Individual ABM simulations are initialized from four distinct multiplex immunohistochemistry (mIHC) slides, and immune related parameter rates are generated using Latin Hypercube Sampling.
In silico simulations suggest that radiation-induced cancer cell death alone is insufficient to clear a tumor with WTRT. However, explicit consideration of radiation-induced anti-tumor immunity synergizes with radiation cytotoxicity to eradicate tumors. Similarly, SFRT-GRID is successful with radiation-induced anti-tumor immunity, and, for some pre-treatment TIME compositions and modeling parameters, SFRT-GRID might be superior to WTRT in providing tumor control.
This study demonstrates the pivotal role of the radiation-induced anti-tumor immunity. Prolonged fractionated treatment schedules may counteract early immune recruitment, which may be protected by SFRT-facilitated immune reservoirs. Different biological responses and treatment outcomes are observed based on pre-treatment TIME composition and model parameters. A rigorous analysis and model calibration for different tumor types and immune infiltration states is required before any conclusions can be drawn for clinical translation.
肿瘤与免疫的相互作用塑造了一个正在发展的肿瘤及其肿瘤免疫微环境（TIME），导致肿瘤浸润程度不同，要么是浸润良好、免疫炎症活跃的肿瘤床，要么是浸润程度低的免疫荒漠。TIME 的预处理免疫构成与治疗结果相关；免疫炎症活跃的肿瘤对放疗和免疫治疗的反应通常优于非炎症肿瘤。然而，放疗已知会引起相反的免疫后果，导致免疫刺激和抑制反应。事实上，人们认为放射诱导的肿瘤杀伤免疫反应会被随后的放射治疗所抑制。因此，可以想象，通过网格块（SFRT-GRID）或晶格放疗进行空间分割放疗（SFRT），以创建低剂量或高剂量暴露区域，可能会为肿瘤免疫微环境创造保护性储库，从而保留对放疗成功至关重要的抗肿瘤免疫反应。
我们开发了一个基于主体的肿瘤-免疫相互作用模型（ABM），用于研究全肿瘤放疗（WTRT）和 SFRT-GRID 后的免疫后果和临床结果。ABM 在概念上进行了校准，使得未经治疗的肿瘤逃避免疫监测并生长到临床检测。个体 ABM 模拟从四个不同的多重免疫组化（mIHC）幻灯片初始化，使用拉丁超立方抽样生成免疫相关参数率。
计算机模拟表明，单独的放射诱导癌细胞死亡不足以用 WTRT 清除肿瘤。然而，明确考虑放射诱导的抗肿瘤免疫与放射细胞毒性协同作用可根除肿瘤。同样，SFRT-GRID 对放射诱导的抗肿瘤免疫有效，并且对于某些预处理 TIME 组成和建模参数，SFRT-GRID 在提供肿瘤控制方面可能优于 WTRT。
本研究表明放射诱导的抗肿瘤免疫的关键作用。延长的分割治疗方案可能会抵消早期的免疫募集，而这可能会受到 SFRT 促进的免疫储库的保护。不同的生物学反应和治疗结果是根据预处理 TIME 组成和模型参数观察到的。在得出任何临床转化的结论之前，需要对不同的肿瘤类型和免疫浸润状态进行严格的分析和模型校准。
