Reference Detail

Ref Type

Journal Article

PMID

(36456601)

Authors

Miao XY, Wu H, Ye BC, Yi QW, Lin FN, Wang YL, Ren CL, Jiang YF, Li A

Title

Non‑small cell lung cancer carrying PBRM1 mutation suggests an immunologically cold phenotype leading to immunotherapy failure even with high TMB.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Scientific reports	12	1	2022 Dec 01	20734	Sci Rep

URL

Abstract Text

High tumor mutation load (TMB-H, or TMB ≥ 10) has been approved by the U.S. FDA as a biomarker for pembrolizumab treatment of solid tumors, including non‑small cell lung cancer (NSCLC). Patients with cancer who have immunotherapy-resistant gene mutations cannot achieve clinical benefits even in TMB-H. In this study, we aimed to identify gene mutations associated with immunotherapy resistance and further informed mechanisms in NSCLC. A combined cohort of 350 immune checkpoint blockade-treated patients from Memorial Sloan Kettering Cancer Center (MSKCC) was used to identify genes whose mutations could negatively influence immunotherapy efficacy. An external NSCLC cohort for which profession-free survival (PFS) data were available was used for independent validation. CIBERSORT algorithms were used to characterize tumor immune infiltrating patterns. Immunogenomic features were analysed in the TCGA NSCLC cohort. We observed that PBRM1 mutations independently and negatively influence immunotherapy efficacy. Survival analysis showed that the overall survival (OS) and PFS of patients with PBRM1 mutations (MT) were significantly shorter than the wild type (WT). Moreover, compared with PBRM1-WT/TMB-H group, OS was worse in the PBRM1-MT/TMB-H group. Notably, in patients with TMB-H/PBRM1-MT, it was equal to that in the low-TMB group. The CIBERSORT algorithm further confirmed that the immune infiltration abundance of CD8+ T cells and activated CD4+ memory T was significantly lower in the MT group. Immunogenomic differences were observed in terms of immune signatures, T-cell receptor repertoire, and immune-related genes between WT and MT groups. Nevertheless, we noticed an inverse relationship, given that MT tumors had a higher TMB than the WT group in MSKCC and TCGA cohort. In conclusion, our study revealed that NSCLC with PBRM1 mutation might be an immunologically cold phenotype and exhibited immunotherapy resistance. NSCLC with PBRM1 mutation might be misclassified as immunoresponsive based on TMB.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PBRM1 mutant	lung non-small cell carcinoma	predicted - resistant	unspecified PD-L1 antibody	Clinical Study - Cohort	Actionable	In a clinical study, treatment with either an anti-PD-1 or anti-PD-L1 therapy resulted in a significantly shorter overall survival (p=0.0057) and progression-free survival (p=0.03) in patients with non-small cell lung cancer harboring a PBRM1 mutation compared to patients with wild-type PBRM1 (PMID: 36456601).	36456601
PBRM1 mutant	lung non-small cell carcinoma	predicted - resistant	unspecified PD-1 antibody	Clinical Study - Cohort	Actionable	In a clinical study, treatment with either an anti-PD-1 or anti-PD-L1 therapy resulted in a significantly shorter overall survival (p=0.0057) and progression-free survival (p=0.03) in patients with non-small cell lung cancer harboring a PBRM1 mutation compared to patients with wild-type PBRM1 (PMID: 36456601).	36456601