Abstract A58: JAK1 deficiency as a novel mechanism of tumor immune escape in uterine cancer

Recognition of MHC class I antigens on the surface of tumor cells is an essential process in the effector phase of CD8 + cytotoxic T lymphocyte (CTL)-mediated anti-tumor response. Presentation of MHC class I antigens on tumor cells is regulated by the JAK1/JAK2-mediated interferon-γ signaling pathway. We analyzed the targeted exome sequencing data of 3,274 human tumors from 48 different tissues in the Total Cancer Care (TCC) tumor bank and found JAK1 truncating mutations in 36 of 635 gynecologic tumors. The highest JAK1 truncating mutation rate (9.5%) was found in endometrial cancer. These truncating mutations result in the loss of the JAK1 protein tyrosine kinase (PTK) domain that is located in the C-terminal region. JAK1 truncating mutations in cancer cell lines of the Cancer Cell Line Encyclopedia (CCLE) databank also occur most often in endometrial cancer cells. Analysis of mutation sites identified three mutation hot spots. Re-sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed JAK1 mutations and revealed that these JAK1 mutations are somatic. Besides JAK1, recurrent JAK2 loss-of-function (LOF) mutations were also found in TCC tumors but at lower rates. Similar to JAK1, the highest rate of LOF JAK2 mutations was found in endometrial/uterine cancer. No JAK1 or JAK2 truncating mutation was identified in 130 samples from hematological malignancies. Functional assays showed that JAK1 deficient cancer cells were defective in interferon-γ-induced expression of tumor antigen processing machinery proteins LMP2 and TAP1 and cell surface expression of HLA molecules. These data identify recurrent JAK1 deficiency in endometrial cancer that impairs tumor antigen presentation by the MHC class I complex to CTLs. While PTKs have been perceived mostly as oncogenes and PTK inhibitors, including JAK inhibitors, have been developed for cancer therapy, our findings suggest that JAK1 is a novel tumor suppressor and that LOF JAK1 mutations allow tumor immune escape. Our findings also raise caution about the use of JAK inhibitors as therapeutic agents in solid tumors. Citation Format: Yuan Ren, Yonghong Zhang, Richard Z. Liu, David A. Fenstermacher, Kenneth L. Wright, Jamie K. Teer, Jie Wu. JAK1 deficiency as a novel mechanism of tumor immune escape in uterine cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A58.