Stereotactic Body Radiotherapy Is Effective in Modifying the Tumor Genome and Tumor Immune Microenvironment in Non-Small Cell Lung Cancer or Lung Metastatic Carcinoma

Abstract

Background and PurposeTo directly reveal the change in genome mutation, RNA transcript of tumor cells, and tumor microenvironment (TME) after stereotactic body radiotherapy (SBRT) in paired human lung tumor specimens.Materials and MethodsPaired tumor samples were collected from 10 patients with non-small cell lung cancer (NSCLC) or lung metastatic carcinoma within a week before and after SBRT. DNA and RNA of tumor tissues was extracted from the paired samples. Whole-exome and RNA sequencing assays were performed by next-generation sequencing. Gene mutation, genomic expression, T-cell receptor (TCR) repertoire, and profiling of tumor-infiltrating immune cells were analyzed through bioinformatics analysis in paired tumor samples. CD8+ T-cell infiltration and PD-L1 expressions were detected by immunostaining in tumor tissues.ResultsThe diversity of TCR repertoire and PD-L1 expression increased significantly in the TME, and the most enriched term of the gene ontology analysis was the immune response gene after receiving SBRT. SBRT induced neo-mutation of genes in tumor cells but did not increase tumor mutation burden in tumor tissues. TME displayed complex immune cell changes and infiltration and expression of immune-regulating factors such as C-X-C motif chemokine (CXCL) 10, CXCL16, interferons (IFNs), and IFN receptors. CD8+ T-cells in tumor tissues did not improve significantly after SBRT while the infiltrating TH1 and TH2 cells decreased remarkably.ConclusionSBRT improved the TCR repertoire diversity and PD-L1 expression in the TME and induced neo-mutation of genes in tumor cells but did not increase CD8+ T-cell infiltration and IFN expression in the tumor tissue within a week.

Immunotherapy in unresectable stage III non-small-cell lung cancer: state of the art and novel therapeutic approaches

“…115 Both RT and SBRT increase levels of T-regulatory cells and programmed deathligand 1 (PD-L1), impairing T-cell activation. [116][117][118] SBRT increases the transforming growth factor-b (TGF-b) hampering T-cell function. 119 Both SBRT and RT result in neoantigen production and higher expression of calreticulin on the tumor cell surface, enhancing T-cell activation.…”

“…18,120 SBRT increases non-synonymous mutation inducing tumor-specific neoantigen development. 116 SBRT promotes the expression of major histocompatibility complex (MHC) class 1 and of immunogenic cell surface markers such as ICAM-1 and Fas, and increases the diversity of T-cell receptor repertoire in the TME. 121,122 SBRT induces immunogenic cell death (ICD), thus promoting the maturation of dendritic cells, T-cell activation and natural killer (NK) cell priming.…”

“…RT increases also: the serine/glycine metabolism in the tumor microenvironment (TME), resulting in higher levels of interleukin 1b (IL-1b) and M2 macrophages,72 myeloid-derived suppressor cells in the TME71 and CD73 expression 115. Both RT and SBRT increase levels of T-regulatory cells and programmed deathligand 1 (PD-L1), impairing T-cell activation [116][117][118]. SBRT increases the transforming growth factor-b (TGF-b) hampering T-cell function 119.…”

“…Both SBRT and RT result in neoantigen production and higher expression of calreticulin on the tumor cell surface, enhancing T-cell activation 18,120. SBRT increases non-synonymous mutation inducing tumor-specific neoantigen development 116. SBRT promotes the expression of major histocompatibility complex (MHC) class 1 and of immunogenic cell surface markers such as ICAM-1 and Fas, and increases the diversity of T-cell receptor repertoire in the TME 121,122.…”

Effect of stereotactic radiotherapy on immune microenvironment of lung cancer

“…However, the radiobiological mechanism of SRT has not been fully elucidated. Recent studies have reported that SRT changes the tumor microenvironment (TME) (5)(6)(7), activating the immune system via in situ immunization and releasing antigens into the blood, promoting antigen-antibody responses, and inducing apoptosis of tumor cells through anti-tumor immunity (8) and vascular injury (9). Dose fractionation of SRT results in different effects on the immune microenvironment (10), and the TME after SRT also changes over time, both of which have an impact on the effect of SRT combined with immunotherapy.…”