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Lung cancer is one of the fastest growing malignant tumors in the world with the fastest growth in morbidity and mortality. In my country, the incidence and mortality rate of lung cancer rank first [1].
In recent years, immune checkpoint blockade therapy represented by PD-1 inhibitors has greatly changed the pattern of tumor treatment. Several recent clinical trials have shown that PD-1 and PD-L1 inhibitors have significantly improved the survival prognosis of non-small cell lung cancer patients [2-4], but 80% of patients with are still not sensitive to this immunotherapy [5].
Therefore, developing biomarker that can predict the efficacy of PD-1 and PD-L1 inhibitors is crucial to determine the benefit population for the improvement of the prognosis of non-small cell lung cancer.
study shows that non-small cell lung cancer responds well to immunotherapy when more than 50% of tumor cells express PD-L1 [6]. However, PD-L1 has great heterogeneity in time and space due to its dynamic expression characteristics, so it is particularly important to develop other indicators that accurately predict immunotherapy response.
Tumor mutation load (TMB) is the total number of non-synonymous mutations in each sequencing coding region of the tumor genome. High TMB has been recommended by the NCCN guide as a marker for immunotherapy for some tumors (for example: gastric cancer , colon cancer ) for immunotherapy.
In non-small cell lung cancer, several clinical trials have shown that high TMB is related to the therapeutic effect of PD-1 inhibitors, but have not shown consistent survival benefits. Therefore, it is still uncertain whether TMB can be used as an indicator for the prediction of the efficacy of immunotherapy for non-small cell lung cancer.
Recently, a research team led by Mark M. Awad of the Dana-Farber Cancer Institute in Boston published an important research result on JAMA Oncology.
They confirmed the importance of TMB in the prediction of immunotherapy for non-small cell lung cancer, and found the optimal threshold for TMB to predict the therapeutic effect of PD-1 and PD-L1 inhibitors in patients with non-small cell lung cancer, and explained the mechanism of high TMB related to good therapeutic effect of PD-1 or PD-L1 inhibitors [7].
This study is of great reference value for the precise treatment of non-small cell lung cancer immunotherapy.
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To confirm the correlation between TMB and the therapeutic effect of PD-1 or PD-L1 inhibitors, the researchers included three cohort data, including 3591 non-small cell lung cancer samples with tumor genomic analysis and complete histological data, and calculated the median (9.8mut/Mb) of .
Subsequently, in order to analyze whether TMB levels are related to the therapeutic effect of PD-1 or PD-L1 inhibitors, the researchers included 1,552 patients with non-small cell lung cancer who received PD-1 or PD-L1 inhibitors and found that among these patients who received PD-1 or PD-L1 inhibitors, TMB levels in patients with good immunotherapy were significantly higher than those with poor treatment effects.
Based on this result, the researchers asked a question: How much can the TMB level be achieved to predict the effect of immunotherapy?
To answer the above questions, the researchers standardized the TMB levels of these patients, constructed a fitted regression model, and function modeled the outcome using PD-1 or PD-L1 inhibitor responses.
Results show that the cutoff value of TMB is 19mut/Mb, and the overall survival (OS, 36.1 months vs. 12.4 months vs. 12.4 months) and overall survival (OS, 36.1 months vs. 12.4 months) and . Therefore, 9mut/Mb can be used as the TMB cutoff value for predicting immunotherapy response .
High TMB is related to PFS and OS
Previous studies have shown that PD-L1 is related to the efficacy of PD-1 inhibitors. So is the predictive effect of TMB in patients with non-small cell lung cancer with different PD-L1 expression levels different?
To solve this question, the researchers divided the patients into 3 groups based on the PD-L1 expression level: 1%, 1%-49% and ≥50%, and compared the therapeutic responses of low TMB and high TMB patients to PD-1 or PD-L1 inhibitors in different subgroups.
results show that for all patients with non-small cell lung cancer at different levels of PD-L1, high TMB indicates a good objective response rate, progression-free survival and overall survival. Therefore, TMB has a good predictive effect on the treatment response of PD-1 or PD-L1 inhibitors in patients with non-small cell lung cancer with different PD-L1 expression. In different PD-L1 expression subgroups, TMB status and the correlation between the treatment response of PD-1 or PD-L1 inhibitors in patients with non-small cell lung cancer
What is the mechanism of TMB related to the treatment response of PD-1 or PD-L1 inhibitors in non-small cell lung cancer?
By performing multiple immunofluorescence detection of the immune markers CD8, Foxp3, PD-1 and PD-L1 on non-small cell lung cancer tissue samples, it was found that in samples with high levels of TMB, the number of CD8-positive and PD1-positive T cells increased significantly in the tumor, tumor-stromal junction and all tissues, while Foxp3-positive cells had no significant correlation with TMB levels .
The ratio of CD8+, PD1+, FOXP3+ and CD8+PD1+ cells in patients with different TMB levels
In addition, the researchers analyzed whether tissue samples of patients with different TMBs had different mutations and transcriptome changes, and conducted subgroup analysis of squamous non-small cell lung cancer and non-squamous non-small cell lung cancer.
mutation spectrum results show that for non-squamous non-small cell lung cancer, high TMB tumors have higher TP53, KEAP1, BRAF and DNA damage repair genes (ATM, BRCA1, BRCA2, ATR and MSH2) mutation ; for squamous non-small cell lung cancer, KRAS and KEAP1 mutations, KRAS and STK11 mutations cannot coexist in high TMB tumors, while the coexistence of KRAS and KEAP1 mutations and the coexistence of KRAS and STK11 mutations are all related to immune checkpoint inhibitor resistance. Therefore, squamous non-small cell lung cancer with high TMB in may be more sensitive to PD-1 or PD-L1 inhibitor treatment .
transcriptome spectrum results show that for non-squamous non-small cell lung cancer, pathways such as MHC-II, IL-7, and DNA damage repair were significantly upregulated in tumors with high TMB; for squamous non-small cell lung cancer, antigen processing and presentation, chemokine transduction and NK cell-mediated cytotoxic related pathways were significantly enriched in tumors with high TMB.
In short, in non-small cell lung cancer, high levels of TMB are positively correlated with favorable features of immunotherapy such as increased immune infiltration and genomic spectrum alteration.
This study provides an effective biomarker for immunotherapy decisions for non-small cell lung cancer, determines the judgment criteria for the treatment of high TMB as an anti-PD-1 or PD-L1 inhibitor, and clarifies the mechanism of good efficacy of PD-1 or PD-L1 inhibitors in high TMB patients, which has high guiding significance for the "precision treatment" of non-small cell lung cancer immunotherapy.
