A research article describing a novel biomarker for immune checkpoint inhibitors in human cancer, entitled “Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway” was published online ahead of print in the scientific journal J Immunother Cancer on December 6, 2023.

Immune checkpoint inhibitors (ICIs) mainly include antibodies that targeting programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). ICIs immunotherapies have revolutionized the treatment of patients with a wide range of advanced cancers, including malignant melanoma, renal cell carcinoma, non-small cell lung cancer, breast cancer, gastric carcinoma. However, only a minority (approximately 20%) of cancer patients benefit from ICIs immunotherapy, it is of vital significance to identify patients who are more likely to benefit from ICIs.

SETD2 is the sole histone methyltransferase responsible for the trimethylation of histone H3 at lysine 36 (H3K36me3) and plays a critical role through H3K36me3. Genomic mutations of SETD2 are prevalent in ~5% of human cancers and promotes tumor progression and metastasis, including clear cell renal cell carcinoma, pancreatic cancer, colorectal cancer, prostate cancer and breast cancer. However, no small molecules or antibodies that specifically target SETD2-deficient tumors and show therapeutic potential have been developed.

To investigate whether SETD2 gene is associated with immune therapy of human cancers, a research team led by Prof. WANG Yuexiang from Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences queried a queue containing 1662 ICIs immunotherapy treated cancer patients. By analyzing patient prognosis and omics datasets, 127 genes showed correlations with beneficial effects of immunotherapy. The top genes included known predictive biomarkers for ICIs therapy, including TP53, PAK7, TET1, PTPRD/PTPRT and STK1. SETD2 ranked among the top three hits of the 127 genes. Patients with inactivating mutations in SETD2 had more favorable outcomes from immunotherapy.

Functional experiments proved that murine syngeneic tumors harboring Setd2 inactivation are sensitive to ICIs. By bulk and single-cell RNA-seq, the researchers further revealed that SETD2 inactivation reprograms intratumoral immune cells and inflames the tumor microenvironment. Mechanistically, via an integrated multiomics analysis using ATAC-seq, ChIP-seq and RNA-seq, the research team demonstrated that SETD2 inactivation reduces NR2F1 transcription by impairing H3K36me3 deposition and chromatin accessibility, which activates the STAT1 signaling pathway to promote chemokines and PD-L1 expression and enhance antigen presentation.

These findings provide novel insights into the biology of SETD2 inactivation regulation and reveal a new potential therapeutic biomarker for ICIs immunotherapy in various refractory cancers, such as pancreatic cancer, melanoma and renal cancer.

The research was supported by Prof. WANG Linhui from Changhai Hospital. This project was financially supported by National Natural Science Foundation of China, Ministry of Science and Technology of China, Science and Technology Commission of Shanghai Municipality, and Chinese Academy of Sciences.