Tumor mutational burden presents limiting effects on predicting the efficacy of immune checkpoint inhibitors and prognostic assessment in adrenocortical carcinoma

Abstract

Background Adrenocortical carcinoma (ACC) is a highly malignant urologic cancer and tends to metastasize. Although immune checkpoint inhibitors (ICIs) bring a glimmer of light to conquer ACC, only a fraction of patients have benefit from ICIs treatment. It is well known that tumor mutational burden (TMB) is closely associated with the efficacy and response rate of immunotherapy. However, its roles in ACC were not investigated. Methods Using somatic mutations data of 92 ACC samples in TCGA database, we calculated their TMB values by the ‘maftools’ package in R software (Ver 3.6.3). To explore the roles of TMB in ICIs therapy, we have addressed this issue from three perspectives. First, the effects of TMB levels on tumor immune microenvironment (TIM) were analyzed through CIBERSORT algorithm, ssGSEA method and TIMER web server. Second, we investigated the expressive correlations between TMB level and five pivotal immune checkpoints based on Pearson coefficient. Third, the difference in TIDE score between high- and low-TMB groups was compared. The prognostic value of TMB was also evaluated. Besides, GSEA was performed to determine the changes in the activities of signaling pathways caused by TMB. Results TMB values in ACC samples were not high. The average of total mutation counts in each sample was only 21.5. High TMB could lead metabolic reprogramming and poor survival outcomes. However, it was unable to affect the infiltration levels of lymphocytes, and failed to facilitate the activities of immune-related pathways. Regarding immune checkpoints (ICs), only PD-L1 upregulation could result in a good prognosis, and TMB level did not correlate with the expressions of other ICs except for LAG3. There was no significant difference in TIDE score between high- and low-TMB groups. Combining the present results and previous study, we speculated that inadequate stimulation for neoantigens formation, intrinsic immune-resistance and special genomic alterations were three possible reasons for TMB limiting functions in TIM and ICIs. Besides, TMB was toughly applied in clinical practice due to its high cost of determination and non-universal definition of high TMB. Conclusions TMB presents limiting effects on prediction for ICIs efficacy and prognostic assessment for ACC patients.

Cuproptosis regulatory genes greatly contribute to clinical assessments of hepatocellular carcinoma

“…7 H-L). Despite the negative result observing in TMB, given that inadequate stimulation for neoantigens formation, high cost of determination and false-negative response population [ 60 , 61 ], whether TMB is a valid predictor is controversial [ 62 ]. In contrast, high expression levels of ICs [ 63 , 64 ], low TIDE score [ 26 ], and analytical results of the IMvigor 210 cohort supported the associations between CR risk score and ICIs efficacy.…”

Establishing a predictive model for tumor mutation burden status based on CT radiomics and clinical features of non-small cell lung cancer patients

“…Although ICIs have transformed treatment regimens for a variety of cancers ( 4 , 18 , 19 , 40 ), including NSCLC, not all patients respond to immunotherapy in the same way ( 10 , 26 , 41 - 45 ). Therefore, the identification of biomarkers that predict ICI efficacy will benefit to improve the prognosis of NSCLC patients ( 16 , 40 ).…”

“…Radiomics is a research method combining imaging, artificial intelligence, and big data, which has a wide range of applications ( 29 , 52 ). At present, quantitative analysis based on CT images has been involved in the diagnosis, efficacy evaluation, and prognosis of lung diseases ( 26 , 39 ). Different from traditional imaging, radiomics can extract thousands of features and contains a huge amount of information, which can reflect the lesion image information at multiple levels and from multiple angles.…”

“…The TMB status of tumors is heterogeneous; for example, chemotherapy may lead to the conversion of low TMB (TMB-L) to TMB-H in some lung cancer patients ( 8 , 10 , 26 ). Therefore, accurate and rapid detection of TMB status is beneficial for doctors to determine the right patient and appropriate time to use immunotherapy in NSCLC ( 15 ).…”