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

Abstract

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.

Dysregulation of SWI/SNF Chromatin Remodelers in NSCLC: Its Influence on Cancer Therapies including Immunotherapy

“…There are two studies assessing the relationship between loss of PBRM1 and response to ICI treatment. Results from the two studies consistently supported the notion that deficiency of the PBRM1 subunits might be a negative biomarker for the ICI response [ 118 , 119 ]. Interestingly, results from two reports about the relationship between deficiency of ARID subunits and response to ICI treatment showed that there was a positive correlation with higher median overall survival (MOS) and overall survival (OS) in NSCLC, with mutations of ARID1 accompanying a higher TMB and higher PD-L1 expression [ 115 , 117 ].…”

“…As mentioned above, the elevated EZH2 activity in the tumor cell with the alteration of SWI and SNF subunits suppresses the function of Th1-type chemokines and IFN-g-responsive genes. One possibility is that the uncontrolled PRC2 activity may be partially responsible for the cold immunity in some SWI/SNF-deficient tumors, even though TMB was peculiarly high in some of these tumors [ 118 , 119 ]. Numerous studies have been carried out to test combination therapy to overcome the resistance of immunotherapy.…”