Abstract
There is currently no reliable biomarker to predict who would benefit from anti-PD-1/PD-L1 inhibitors. We comprehensively analyzed the immunogenomic properties in The Cancer Genome Atlas (TCGA) according to the classification of tumor into four groups based on PD-L1 status and tumor-infiltrating lymphocyte recruitment (TIL), a combination that has been suggested to be a theoretically reliable biomarker of anti-PD-1/PD-L1 inhibitors. The RNA expression levels of PD-L1 and CD8A in the samples in the pan-cancer database of TCGA (N = 9,677) were analyzed. Based on their median values, the samples were classified into four tumor microenvironment immune types (TMIT). The mutational profiles, PD-L1 amplification, and viral association of the samples were compared according to the four TMITs. The proportions of TMIT I, defined by high PD-L1 and CD8A expression, were high in lung adenocarcinoma (67.1%) and kidney clear cell carcinoma (64.8%) among solid cancers. The number of somatic mutations and the proportion of microsatellite instable-high tumor in TMIT I were significantly higher than those in other TMITs, respectively (P < 0.001). PD-L1 amplification and oncogenic virus infection were significantly associated with TMIT I, respectively (P < 0.001). A multivariate analysis confirmed that the number of somatic mutations, PD-L1 amplification, and Epstein-Barr virus/human papillomavirus infection were independently associated with TMIT I. TMIT I is associated with a high mutational burden, PD-L1 amplification, and oncogenic viral infection. This integrative analysis highlights the importance of the assessment of both PD-L1 expression and TIL recruitment to predict responders to immune checkpoint inhibitors. Clin Cancer Res; 22(9); 2261-70. ©2016 AACRSee related commentary by Schalper et al., p. 2102.
Highlights
A recent strategy targeting immune checkpoints such as CTLA-4 and PD-1/PD-L1 shows promising clinical benefits and introduces a paradigm shift in cancer treatment
A multivariate analysis confirmed that the number of somatic mutations, PD-L1 amplification, and Epstein–Barr virus/human papillomavirus infection were independently associated with tumor microenvironment immune types (TMIT) I
TMIT I is associated with a high mutational burden, PD-L1 amplification, and oncogenic viral infection
Summary
A recent strategy targeting immune checkpoints such as CTLA-4 and PD-1/PD-L1 shows promising clinical benefits and introduces a paradigm shift in cancer treatment. Recent advances in immuno-genomics have shown that tumors with a high mutational burden, abundant neoantigen, and microsatellite (MSI)-high status are associated with a good response to anti-PD-1/PD-L1 therapy [8,9,10,11,12,13,14]. Oncogenic viruses such as Epstein–Barr virus (EBV) or human papillomavirus (HPV) are associated with an inflamed TME, and a favorable clinical outcome in response to anti-PD-1/PD-L1 therapy would be expected [10, 15]. Because of the complex nature of tumor immunity, a comprehensive immuno-genomic analysis that include analyses of the interaction between the tumor and TIL in the TME and investigations of the underlying reasons for the promotion of tumor immunogenicity is needed
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