Tumor Cell-Intrinsic Circular RNA CircFNDC3B Attenuates CD8+ T Cells Infiltration in Non-Small Cell Lung Cancer

Tumor-infiltrating CD8 ⁺ T cells are related with a satisfactory immunotherapy efficacy and a survival benefit. However, the mechanisms underlying differential infiltration levels are largely unknown, especially the role of circular RNAs (circRNAs) involving in CD8 ⁺ T cells infiltration remain poorly understood. Here, we identify 9912 distinct circRNAs from four paired normal and tumorous tissues of non-small cell lung cancer (NSCLC). We discover that circFNDC3B, derived from exons 2 and 3 of the FNDC3B gene, is significantly upregulated in NSCLC. TFⅡ-I interacting with STAT1 could function as an activator of transcription, facilitating CXCL10 and CXCL11 expression. However, circFNDC3B could bind to TFⅡ-I forming an RNA-protein complexus, thereby competitively inhibited the interaction between TFⅡ-I and STAT1, decreased the level of CXCL10 and CXCL11, and restricted infiltration of CD8 ⁺ T cells eventually. Meanwhile, the mouse circFndc3b ortholog is also inversely correlated with the infiltration of CD8 ⁺ T cells, attenuating the PD-1 blockade therapy’s effectiveness. These results demonstrate a pivotal role of tumor cell-intrinsic circRNA in immune infiltration and validate circFNDC3B as a potential target to develop a better effective immunotherapy strategy of NSCLC.