SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges

Yu Chen, Min Gao, Zhaoqin Huang, Jinming Yu, Xiangjiao Meng, Yu Chen, Min Gao, Zhaoqin Huang, Jinming Yu, Xiangjiao Meng

Abstract

Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1), and others have shown potent clinical efficacy and have revolutionized the treatment protocols of a broad spectrum of tumor types, especially non-small-cell lung cancer (NSCLC). Despite the substantial optimism of treatment with PD-1/PD-L1 inhibitors, there is still a large proportion of patients with advanced NSCLC who are resistant to the inhibitors. Preclinical and clinical trials have demonstrated that radiotherapy can induce a systemic antitumor immune response and have a great potential to sensitize refractory "cold" tumors to immunotherapy. Stereotactic body radiation therapy (SBRT), as a novel radiotherapy modality that delivers higher doses to smaller target lesions, has shown favorable antitumor effects with significantly improved local and distant control as well as better survival benefits in various solid tumors. Notably, research has revealed that SBRT is superior to conventional radiotherapy, possibly because of its more powerful immune activation effects. Thus, PD-1/PD-L1 inhibitors combined with SBRT instead of conventional radiotherapy might be more promising to fight against NSCLC, further achieving more favorable survival outcomes. In this review, we focus on the underlying mechanisms and recent advances of SBRT combined with PD-1/PD-L1 inhibitors with an emphasis on some future challenges and directions that warrant further investigation.

Keywords: Advances; Challenges; Combination treatment; Non-small-cell lung cancer (NSCLC); PD-1/PD-L1 inhibitors; Stereotactic body radiation therapy (SBRT).

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The specific mechanisms of SBRT combined with PD-1/PD-L1 inhibitors. The supportive modulatory mechanisms include upregulation of immunogenic cell surface markers such as ICAM-1, MHC-1 and Fas, induction of immunogenic cell death, release of tumor antigen and cytokines as IFN, TNFα, IL-1, IL-6, and so on, and enhanced homing of immune cells to tumors. Notably, the activated immune response can further act on distant nonirradiated metastases to appreciably inhibit metastases progression. Besides, SBRT can also induce immunosuppressive effects involving increased release of negative cytokines like TGFβ, accumulation of radioresistant suppressor cells, and upregulation of PD-L1 expression. The integration of PD-1/PD-L1 inhibitors to SBRT could not only enhance positive immunoregulation, but also significantly attenuate negative immune resistance, thus achieving potent anti-tumor immunity. Challenges exist to eliminate the remained suppressive effects

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