Nowosielska Ewa M, Cheda Aneta, Pociegiel Mateusz, Cheda Lukasz, Szymański Paweł, Wiedlocha Antoni
Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163 Warsaw, Poland.
National Centre for Nuclear Research Radioisotope Centre POLATOM, 7A Soltana St., 05-400 Otwock, Poland.
Int J Mol Sci. 2021 Jun 11;22(12):6309. doi: 10.3390/ijms22126309.
Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer death worldwide. Recently, targeting molecules whose functions are associated with tumorigenesis has become a game changing adjunct to standard anti-cancer therapy. As evidenced by the results of preclinical and clinical investigations, whole-body irradiations (WBI) with X-rays at less than 0.1-0.2 Gy per fraction can induce remissions of various neoplasms without inciting adverse side effects of conventional chemo- and radiotherapy. In the present study, a murine model of human NSCLC was employed to evaluate for the first time the anti-neoplastic efficacy of WBI combined with inactivation of CTLA-4, PD-1, and/or HSP90. The results indicate that WBI alone and in conjunction with the inhibition of the function of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) receptor immune checkpoints (ICs) and/or heat shock protein 90 (HSP90) markedly reduced tumorigenesis in mice implanted by three different routes with the syngeneic Lewis lung cancer cells and suppressed clonogenic potential of Lewis lung carcinoma (LLC1) cells in vitro. These results were associated with the relevant changes in the profile of pro- and anti-neoplastic immune cells recruited to the growing tumors and the circulating anti- and pro-inflammatory cytokines. In contrast, inhibition of the tested molecular targets used either separately or in combination with each other did not exert notable anti-neoplastic effects. Moreover, no significant synergistic effects were detected when the inhibitors were applied concurrently with WBI. The obtained results supplemented with further mechanistic explanations provided by future investigations will help design the effective strategies of treatment of lung and other cancers based on inactivation of the immune checkpoint and/or heat shock molecules combined with low-dose radiotherapy.
非小细胞肺癌（NSCLC）仍然是全球癌症死亡的主要原因。最近，靶向与肿瘤发生相关功能的分子已成为标准抗癌治疗中改变游戏规则的辅助手段。临床前和临床研究结果表明，每次分割以低于0.1 - 0.2 Gy的X射线进行全身照射（WBI）可诱导各种肿瘤缓解，而不会引发传统化疗和放疗的不良副作用。在本研究中，首次使用人NSCLC的小鼠模型来评估WBI联合CTLA - 4、PD - 1和/或HSP90失活的抗肿瘤效果。结果表明，单独的WBI以及与细胞毒性T淋巴细胞抗原 - 4（CTLA - 4）和程序性死亡 - 1（PD - 1）受体免疫检查点（ICs）和/或热休克蛋白90（HSP90）功能抑制联合使用时，显著降低了通过三种不同途径植入同基因Lewis肺癌细胞的小鼠的肿瘤发生，并在体外抑制了Lewis肺癌（LLC1）细胞的克隆形成潜力。这些结果与募集到生长肿瘤中的促肿瘤和抗肿瘤免疫细胞谱以及循环中的抗炎和促炎细胞因子的相关变化有关。相比之下，单独或相互组合使用的测试分子靶点的抑制并未产生显著的抗肿瘤作用。此外，当抑制剂与WBI同时应用时，未检测到明显的协同作用。获得的结果以及未来研究提供的进一步机制解释将有助于设计基于免疫检查点和/或热休克分子失活并结合低剂量放疗的肺癌和其他癌症的有效治疗策略。
