YAP1 Expression in SCLC Defines a Distinct Subtype With T-cell–Inflamed Phenotype

Abstract

Introduction: The clinical and biological significance of the newly described SCLC subtypes, SCLC-A, SCLC-N, SCLC-Y, and SCLC-P, defined by the dominant expression of transcription factors ASCL1, NeuroD1, YAP1, and POU2F3, respectively, remain to be established. Methods:We generated new RNA sequencing expression data from a discovery set of 59 archival tumor samples of neuroendocrine tumors and new protein expression data by immunohistochemistry in 99 SCLC cases. We validated the findings from this discovery set in two independent validation sets consisting of RNA sequencing data generated from 51 SCLC cell lines and 81 primary human SCLC samples.Results: We successfully classified 71.8% of SCLC and 18.5% of carcinoid cases in our discovery set into one of the four SCLC subtypes. Gene set enrichment analysis for differentially expressed genes between the SCLC survival outliers (top and bottom deciles) matched for clinically relevant prognostic factors revealed substantial upregulation of interferon-g response genes in long-term survivors. The SCLC-Y subtype was associated with high expression of interferon-g response genes, highest weighted score on a validated 18-gene T-cell-inflamed gene expression profile score, and high expression of HLA and T-cell receptor genes. YAP1 protein expression was more prevalent and more intensely expressed in limited-stage versus extensive-stage SCLC (30.6% versus 8.5%; p ¼ 0.0058) indicating good prognosis for the SCLC-Y subtype. We replicated the inflamed phenotype of SCLC-Y in the two independent validation data sets from the SCLC cell lines and tumor samples.Conclusions: SCLC subtyping using transcriptional signaling holds clinical relevance with the inflamed phenotype associated with the SCLC-Y subset.

YAP1 protein expression has variant prognostic significance in small cell lung cancer (SCLC) stratified by histological subtypes

“…[14] For clinical relevance, the putative SCLC-Y subtype was found associated with the inflamed phenotype which might be more likely to benefit from immunotherapy. [30] However, Baine's study based on IHC failed to corroborate that YAP1 represented a distinct subtype in SCLC since YAP1 expression was widely distributed in all subtypes. [31] Furthermore, study by Gay et al also confirmed YAP1 did not exclusively define a subtype.…”

“…There was no significant difference in other clinical parameters including tumor laterality, clinical stage, VALSG stage, treatment modes and patterns of relapse. As for pathological features, we found a significant higher percentage of necrosis in YAP1 positive group with median [IQR] 30 [20,40] vs. 20 [10,30] in YAP1 positive group and negative group respectively (Table 1). Consistent with these results, we observed that the positive rate of YAP1 was significant higher in the small cell components of C-SCLC (C-SCLC vs. P-SCLC, 52.2% vs. 29.1%, P=0.004), male sex (male vs. female, 37.6% vs. 20.7%, P=0.007), patients with age above 60 (age > 60 vs. age≤60, 43.1% vs. 26.6%, P=0.005) and smokers (yes vs. no: 36.9% vs. 24.5%, P=0.042) (Table 2).…”

Small cell lung cancer: a slightly less orphan disease after immunotherapy

“…54 This new classification may have therapeutic implications, and the SCLC-Y subtype is enriched for T-cell inflamed phenotype, high expression of IFN-g response genes and longterm survival, predicting potential clinical benefit of immunotherapy in this subtype. 55 Recently, using RNAseq analysis, it was reported that the distribution of subtypes from the phase III IMpower133 trial was 51% SCLC-A, 23% SCLC-N, 18% SCLC-I inflamed and 7% SCLC-P. Although the trial was not statistically powered for subtype-specific subgroup analyses, the addition of atezolizumab improved the OS across all four subtypes, including a modest trend toward improved OS in SCLC-I relative to each of the other three subtypes that is not observed in the placebo arm.…”

Advances in novel molecular typing and precise treatment strategies for small cell lung cancer

“…Some investigators have further explored the association between YAP1 and immunity. Owonikoko et al ( 28 ) found that SCLCs with YAP1 positive was enriched in long-term survivors, and associated with high expression levels of interferon-γ ( INF-γ ) gene, human leukocyte antigen ( HLA ) gene, and T-cell receptor gene, and high scores of T-cell inflammatory gene expression profile (GEP). They subsequently replicated this inflammatory phenotype using SCLC cell lines and tumor samples in two independent validation datasets ( 28 ).…”

“…Owonikoko et al ( 28 ) found that SCLCs with YAP1 positive was enriched in long-term survivors, and associated with high expression levels of interferon-γ ( INF-γ ) gene, human leukocyte antigen ( HLA ) gene, and T-cell receptor gene, and high scores of T-cell inflammatory gene expression profile (GEP). They subsequently replicated this inflammatory phenotype using SCLC cell lines and tumor samples in two independent validation datasets ( 28 ). Similarly, another study revealed that although SCLC is a cancer with the lowest expression of immune-related genes, SCLC-Y cell lines evidently show a tendency for better antigenic presentation and innate immune response.…”