The Combination of Radiotherapy With Immunotherapy and Potential Predictive Biomarkers for Treatment of Non-Small Cell Lung Cancer Patients

Abstract

Radiotherapy is an effective local treatment modality of NSCLC. Its capabilities of eliminating tumor cells by inducing double strand DNA (dsDNA) damage and modulating anti-tumor immune response in irradiated and nonirradiated sites have been elucidated. The novel ICIs therapy has brought hope to patients resistant to traditional treatment methods, including radiotherapy. The integration of radiotherapy with immunotherapy has shown improved efficacy to control tumor progression and prolong survival in NSCLC. In this context, biomarkers that help choose the most effective treatment modality for individuals and avoid unnecessary toxicities caused by ineffective treatment are urgently needed. This article summarized the effects of radiation in the tumor immune microenvironment and the mechanisms involved. Outcomes of multiple clinical trials investigating immuno-radiotherapy were also discussed here. Furthermore, we outlined the emerging biomarkers for the efficacy of PD-1/PD-L1 blockades and radiation therapy and discussed their predictive value in NSCLC.

Keywords: biomarker; immune checkpoint inhibitor (ICI); immunotherapy; non-small cell lung cancer (NSCLC); radiotherapy.

Figure 1

Mechanisms by which radiation enhances and inhibits immune response. Irradiation of tumor leads to immunogenic cell death and release of tumor neoantigens. Multiple DAMPs secreted from apoptotic tumor cells facilitate the uptake and presentation of neoantigens. Released ATP and exposure of CRT send the ‘find me’ and ‘eat me’ signal to APC and phagocyte respectively. HMGB1 promotes maturation of APC through binding with TLR4. As a result, APC migrates to lymph nodes and presents neoantigens to T cells mediated by MHC pathway. In addition to antigen presentation, type I IFN via cGAS-STING pathway and a variety of other cytokines and chemokines also take part in T cell priming and activation. The activated T cells, especially the CD8⁺ T cells proliferate, home to tumor, and exert their killing effect. Apart from the irradiated tumor site, effector T cells also migrate to distant tumors and drive abscopal effect. However, immune escape appears after radiation, which limits the efficacy of radiation. Upregulation of immune checkpoints, such as CTLA-4 on Tregs and PD-L1 on tumor cells, inhibits the activation and function of T cells. TGF β secreted by Tregs is capable to significantly increase the number of immunosuppressive cells in the TME, including Treg, CAF, MDSC and M2 phenotype macrophage.