Researchers identify an unexpected driver of resistance to cancer immunotherapy

A research team from the University of Hong Kong LKS Faculty of Medicine (HKUMed) has identified an unexpected driver of resistance to cancer immunotherapy: the harmful effect of chronic type I interferon signaling on tumor-killing CD8⁺T cells. These results provided new insights into the development of depleted CD8s⁺ T cells, which no longer effectively limit tumor growth, and have revealed a new target for improved immunotherapy. The research has been published in Cell reports.

Background

Immunotherapy, where drugs reactivate the body’s immune system to fight disease, is an increasingly popular first-line treatment for various cancers. Although many cancer patients have benefited, the majority still do not respond to treatment or rapidly develop resistance to treatment. The current effective response rate of 20% to 30% is the result of many unknown contributing factors.

Cancer is usually controlled by the anti-tumor effector functions of CD8⁺ T cells. When these cancer-fighting T cells run out (depleted CD8⁺ T cells, Tex), the protective response wanes, allowing the tumor to undergo an immune leak and grow out of control. Preventing and reversing Tex is the primary goal of cancer immunotherapy. However, with the terminal development of Tex resistant to immunotherapy, its efficiency is limited to 20-30%. The research aims to understand the drivers of terminal Tex and to discover new therapeutic targets to improve immunotherapy against cancer.

search results

The research team discovered a surprising harmful effect of chronic interferon type I (IFN-I)^[1] exhibition on the development of Tex and resistance to immunotherapy. Cancer patients resistant to immunotherapy also tended to show higher levels of IFN-I signaling.

Through new analysis of public patient datasets, immune cell cultures and animal models, the research team showed that chronic IFN-I signaling drives CD8⁺ Commitment of T cell fate to terminal exhaustion via promotion of lipid peroxidation (LPO), accumulating treatment resistance.

Importance of research

Dr. Heidi Ling Guang Sheng, Assistant Professor, School of Biomedical Sciences, HKUMed and his team have identified that the detrimental pathway IFN-I-LPO can be used to advise patients’ treatment regimens by serving as a biomarker, thus improving the personalization of patient therapy. Moreover, further study of the role of IFN-I opens the way to new treatment options to improve the immunotherapeutic response of patients.

“These research results pave the way for new approaches to improve the effectiveness of cancer immunotherapy. Nevertheless, clinical trials need to be conducted to validate the timing, efficacy, and safety of IFN-I blockade,” Dr. Ling noted.

About the research team

This research was led by Dr. Heidi Ling Guang Sheng, Assistant Professor, School of Biomedical Sciences, HKUMed. Chen Weixin, doctoral student, is the first author, with the help of Teo Jia Ming Nickolas, doctoral student; Yau Siu-wah, research assistant; and Dr. Melody Wong Yee-man, Technical Director, Hong Kong Science and Technology Parks Corporation. Other collaborators included Dr. Lok Chun-nam, Professor Che Chi-ming, State Key Laboratory of Synthetic Chemistry and Department of Chemistry, HKU; Dr Javed Asif, Dr Huang Yuanhua and Professor Stephanie Ma Kwai-yee, School of Biomedical Sciences, HKUMed.