New Biomarker-Driven Strategy Could Help Treat Liver Cancer

A study conducted by the MD Anderson Cancer Center at the University of Texas revealed a cancer-related cell pathway that could be beneficial in reducing side effects and prolonging the duration of immunotherapy in some patients with hepatocellular carcinoma, the most common form of liver cancer.

The researchers looked at a cellular pathway formed when a protein known as interleukin-6 (IL-6) activates an enzyme called Janus kinase 1 (JAK1), as well as the potential of a drug. anti-IL-6 and anti-T-immunoglobulin mucin antibodies. 3 (anti-Tim-3) by increasing immunotherapy. The results of the study were published in the July 15 issue Journal of Clinical Investigation.

The IL-6 / JAK1 pathway is often observed in tumors and may play a role in cancer escape by regulating a crucial cell function in the programmed death ligand 1 (PD-L1), a type of protein known to suppress the immune system.

"Our results demonstrated that anti-IL-6 antibodies combined with anti-Tim-3 antibodies increased T-cell killing effects in murine models," said Li-Chuan Chan, Ph.D., postdoctoral fellow. to the department. of molecular and cellular oncology "We have identified a mechanism regulating the initiation of PD-L1 glycosylation, suggesting that a combination of anti-IL-6 and anti-Tim antibodies -3 is an effective therapeutic strategy guided by a marker. "

The researchers examined the correlation between the expression of IL-6 and PD-L1 in tumor samples from 183 liver patients and found that patients with high IL expression. -6 also had a high expression of PD-L1. Previous studies by MD Anderson had shown that elevated IL-6 levels were badociated with a worse prognosis in patients with liver cancer. The team's new findings suggest that IL-6 is "physiologically significant and clinically relevant" for the expression of PD-L1 in liver cancer.

"We also found that the IL-6 / JAK1 pathway contributed to the phosphorylation of PD-L1, which appeared to be the major immune evasion factor against cancer in a murine model of mice suffering from cancer. liver, "said Chan. "Together, these findings could provide a potential mechanism on how JAK1 activated translocates to other cellular compartments and would warrant further investigation in the future."

The study also highlighted a potential benefit for the reduction of side effects of immunotherapy, which can sometimes reduce the length of time patients can stay on treatment. Immune checkpoint inhibitors have been shown to stimulate serum production of IL-6, which can cause arthritis, Crohn's disease and psoriasiform dermatitis.

"Therefore, blocking the IL-6 pathway could resolve these side effects and prolong the duration of immunotherapy," Chan said.

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Participants in the MD Anderson study were: Chia-Wei Li, Ph.D .; Weiya Xia, M.D .; Jung-Mao Hsu, Ph.D .; Heng-Huan Lee, Ph.D .; Jong-Ho Cha, Ph.D .; Wen-Hao Yang, Ph.D .; Zhengyu Zha, Ph.D .; Seung-Oe Lim, Ph..D .; Chunxiao Liu, Ph.D .; Jielin Liu; Qiongzhu Dong; Yi Yang; Linlin Sun; Yongkun Wei, Ph.D .; Jennifer Hsu, Ph.D .; and Hui Li, all of the Department of Molecular and Cellular Oncology; Mbad Hbadan, Ph.D .; and Ahmed Kaseb, M.D., Department of Gastrointestinal Medical Oncology; and Hesham Amin, M.D., Department of Hematopathology. Mien-Chie Hung, Ph.D., formerly of the Department of Molecular and Cellular Oncology, was the lead author of the paper and served as Ph.D. Thesis dissertation for Chan, T32 fellowship holder in cancer biology.

The study was funded by the National Institutes of Health (P30CA016672, CA211615, U01 CA201777, AI116722 and 5T32CA18692); the Texas Institute of Cancer Prevention and Research (RP160710); The MD Anderson Cancer Center at the University of Texas, the sister institution's fund of the University of Medicine and Hospital of China; the Ministry of Health and Welfare, the Medical Hospital of the University of China (MOHW108-TDU-B-212-124024 and MOHW108-TDU-B-212-122015); the Ministry of Science and Technology's Overseas Post-Doctoral Research Project (MOST 104-2917-I-564-003); the National Research Foundation of Korea (MSIP 2011-0030001); and the MD Anderson Odyssey Scholarship Program.