January 25, 2022

RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity

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featured discovery

eddy yang 2Eddy Shih-Hsin Yang, M.D., Ph.D.The latest winner of the Heersink School of Medicine’s Featured Discovery is Eddy Shih-Hsin Yang, M.D., Ph.D., professor in the Department of Radiation Oncology, and his collaborative team. This initiative celebrates important research from Heersink School of Medicine faculty members.

Yang and his team, including first author and Assistant Professor in the Department of Radiation Oncology Zhuo Zhang, M.D., Ph.D., were recently published in Nature Cancer for their paper “RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity.”

On the study, Yang explains, “This study sheds light on a new mechanism by which RNF2 expressed by triple negative breast cancers can suppress immune-mediated anti-tumor responses.”

“The targeting and deletion of RNF2 results in activation, infiltration, and cooperation of the innate (NK cell) and adaptive (CD-4+ T cell) immune systems and the subsequent durable immune-mediated rejection and clearance of triple negative breast cancer models.”

Zhuo Zhang Photo 3Zhuo Zhang, M.D., Ph.D.Yang said the immune memory response was also induced, which resulted in immune rejection of a second tumor.

These groundbreaking results uncover a new epigenetic reprogramming of the tumor-immune microenvironment that fosters long term anti-tumor immunity and memory.

Zhang said “Our findings provide a potentially new epigenetic target to enhance the immune system given that current available epigenetic drugs are not successful in the clinic.”

The Heersink communications staff sat down with Dr. Yang to gain insights about the research of this study, UAB, and the science community.

Q: What was your most unexpected finding?

Yang: We are very excited to observe that knocking out RNF2 induced such a dramatic and durable immune-mediated rejection of breast cancer but what was unexpected and even more compelling was the fact that this process also generated an immune memory against wild-type cancer. These findings suggest the translational potential of this strategy.

Q: How do you feel your research will impact the science community?

Yang: Current immunotherapies against cancer have yielded dramatic responses and great outcomes for a proportion of patients but unfortunately many do not respond or their cancers become refractory to immunotherapy. Our research uncovers a novel mechanism and strategy to potentially enhance the immune response through a different mechanism that involves the cooperatively between the innate and adaptive immune responses that induces immune memory, which may provide insights into how we can improve upon immunotherapy-based treatments.

Q: What is your research’s relevance to human disease?

Yang: Our research is very relevant to the understanding and potential treatment of the highly aggressive triple negative breast cancer. There are few treatment options for metastatic/refractory TNBC outside of chemotherapy. One type of immunotherapy was previously granted accelerated approval by the FDA but this indication was recently withdrawn. Our discovery provides insights into how RNF2 suppresses the immune system against cancer and how the targeting of RNF2 may be a new strategy to augment the immune response against TNBC. In addition the targeting of RNF2 may be applicable to other tumor types as well.

Q: When did you know you had an important discovery?

Yang: We knew this was an important discovery when we looked at large databases of sequencing data from human cancers and consistently found that RNF2 was one of the top genes that correlated with worse outcomes and lower immune activity. We were very excited when we deleted RNF2 in TNBC models and saw that mice were tumor free for over 400 days. We knew then we were onto something important.

Q: What do you find makes the science community here unique?

Both Drs. Yang and Zhang offered their gratitude for the collaborative nature of research at Heersink School of Medicine, which ultimately led to the success of their study.

Zhang: Most importantly, I would like to appreciate the tremendous support from Drs. Eddy Yang, Jianmei Wu Leavenworth, Zechen Chong, William Britt, Tim Townes, Narendra Wajapeyee, and Barry Sleckman, as well as our staff scientists and the Flow Cytometry, Small Animal Imaging, and Heflin Center for Genomic Sciences core facilities. I feel that UAB with its affiliated Medical School, Cancer Center, Radiation Oncology Department is a collaborative and encouraging research environment.

Yang: What is unique and key to our success has been the collaborative nature and wide breadth of expertise here within the UAB scientific community. Everyone is so open and willing to help and provide their assistance. This was one of the main reasons that attracted me to UAB. As you can see from this work, it could not have been accomplished without the hard work and effort of the whole team, including Drs. Zhang, Leavenworth, Chong, Townes, Britt, Wajapeyee, Sleckman, and others.