July 25, 2024

New Biomarker for Immune Checkpoint Inhibitors Identified in Human Lethal Cancers

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many lethal cancers. However, only a small percentage of patients benefit from this therapy. Therefore, it is crucial to identify patients who are more likely to respond positively to ICIs. A recent study published in the Journal for ImmunoTherapy of Cancer on December 6 has discovered a novel biomarker for ICIs in human cancers.

These proteins play a significant role in regulating the immune response. While ICIs have shown great promise in treating certain cancers, the response rate remains relatively low, around 20%. Identifying biomarkers that can predict a positive response to ICIs is crucial for optimizing treatment outcomes.

The study focused on the histone methyltransferase gene known as SETD2. SETD2 is responsible for the trimethylation of histone H3 at lysine 36 (H3K36me3), which plays a critical role in gene regulation. Mutations in SETD2 have been found in approximately 5% of human cancers and are known to promote tumor progression and metastasis in various cancer types, including clear cell renal cell carcinoma, pancreatic cancer, colorectal cancer, prostate cancer, and breast cancer. However, no targeted therapies have been developed specifically for SETD2-deficient tumors.

To explore the relationship between SETD2 and cancer immunotherapy, a research team led by Prof. Wang Yuexiang from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences analyzed data from 1,662 patients who had received ICIs treatment. Through their analysis of prognosis and omics datasets, the researchers identified 127 genes that correlated with a positive response to immunotherapy. Among these genes, SETD2 was ranked among the top three. Patients with SETD2 inactivating mutations showed more favorable responses to immunotherapy.

Functional experiments confirmed that mice with syngeneic tumors harboring Setd2 inactivation were more sensitive to ICIs. The researchers further investigated the effects of SETD2 inactivation on intratumoral immune cells and the tumor microenvironment through bulk and single-cell RNA-sequencing. They discovered that SETD2 inactivation reprogrammed intratumoral immune cells and caused inflammation in the tumor microenvironment.

By utilizing different multi-omics techniques, such as ATAC-seq, ChIP-seq, and RNA-seq, the researchers found that SETD2 inactivation reduced NR2F1 transcription by impairing H3K36me3 deposition and chromatin accessibility. This, in turn, activated the STAT1 signaling pathway, leading to increased expression of chemokines and PD-L1, thereby improving antigen presentation.

These findings provide valuable insights into the biology of SETD2 inactivation regulation and offer a novel biomarker for identifying cancer patients who may benefit from ICI therapy. This biomarker is particularly relevant for cancers such as pancreatic cancer, melanoma, and renal cancer. Identifying patients who are more likely to respond to ICIs can help optimize treatment strategies and improve outcomes for those with lethal cancers.

1. Source: Coherent Market Insights, Public sources, Desk research
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