Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma.

Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported. An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway. The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy. Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs. The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).

Sun H ，Liu SY ，Zhou JY ，Xu JT ，Zhang HK ，Yan HH ，Huan JJ ，Dai PP ，Xu CR ，Su J ，Guan YF ，Yi X ，Yu RS ，Zhong WZ ，Wu YL ... -  《EBioMedicine》

Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012-24. ©2016 AACR.

Dong ZY ，Zhong WZ ，Zhang XC ，Su J ，Xie Z ，Liu SY ，Tu HY ，Chen HJ ，Sun YL ，Zhou Q ，Yang JJ ，Yang XN ，Lin JX ，Yan HH ，Zhai HR ，Yan LX ，Liao RQ ，Wu SP ，Wu YL ... -  《-》

Combination of tumor mutation burden and immune infiltrates for the prognosis of lung adenocarcinoma.

Tumor mutation burden (TMB) levels are associated with immune infiltrates in the tumor microenvironment and can modulate the responses to immune checkpoint inhibitors (ICIs) in lung adenocarcinoma (LUAD) patients. This study aimed at exploring the potential role of a signature of genes associated with TMB and immune infiltrates and the relevant nomogram in the prognosis of LUAD. The TMB levels in LUAD patients in the Cancer Genome Atlas (TCGA) were analyzed. The differentially expressed genes (DEGs) between the higher- and lower-TMB subgroups were functionally analyzed. The immune-related DEGs and their relationship with immune infiltrates in the tumor environment between two subgroups were analyzed. Nine immune-related DEGs were used to generate a TMB-related immune signature. The sensitivity to immunotherapy in TCGA-LUAD patients was analyzed by immunophenotypic scores (IPS). Subsequently, a nomogram was generated using tumor-related parameters and the signature score. The signature or nomogram values in predicting overall survival (OS) were evaluated and validated in LUAD patients in the GSE30219 and GSE72094. There were 468 DEGs between the higher and lower-TMB subgroups of LUAD patients. The TMB levels were associated positively with the number of immune infiltrates in LUAD patients. Nine DEGs were related to immune infiltrates in the tumor environment. The higher signature scores (high-risk) were associated with poor prognosis of LUAD in the TCGA, which was validated in LUAD patients of the GSE30219 and GSE72094 datasets. Interestingly, the patients in the high-risk group had higher PD-L1 expression in their tumors and the risk scores in LUAD patients. The IPS of LUAD patients in the high-risk group were predicted to benefit from immunotherapy. Finally, the nomogram had high AUC values in predicting the OS of LUAD patients. The TMB-related immune signature or nomogram is valuable for the prognosis of LUAD patients and evaluating their responses to ICIs. These relevant genes may participate into the pathogenesis, ICIs, and drug resistance of LUAD.

Zhao Z ，He B ，Cai Q ，Zhang P ，Peng X ，Zhang Y ，Xie H ，Wang X ... -  《-》

RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer.

Manzano RG ，Catalan-Latorre A ，Brugarolas A 《BMC CANCER》

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohorts PCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

Liu M ，Yang M ，Zhang B ，Xia S ，Zhao J ，Yan L ，Ren Y ，Guo H ，Zhao J ... -  《-》