A UNMC research team, including postdoctoral research associate Muthamil Iniyan Appadurai, PhD, and assistant professor Imayavaramban Lakshmanan, PhD, has identified a novel mechanism that may help explain not only how lung cancer evades the immune system but also uncovered a potential new therapeutic target.
Their findings, recently published in the Journal of Clinical Investigation, focus on an enzyme called ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to proteins.
“This enzyme was highly overexpressed in both mouse lung tumor models and in human lung cancer samples, but it showed minimal expression in normal lung tissue,” said Dr. Lakshmanan, assistant professor in the UNMC Department of Biochemistry and Molecular Biology and a member of the Fred & Pamela Buffett Cancer Center. “That contrast made it a strong candidate for further investigation.”
Drawing on gene expression datasets and in preclinical models, the team identified two primary mechanisms by which ST6GalNAc-I promotes lung cancer progression: by facilitating tumor cells escape from the immune system, and by fueling the formation of new blood vessels, a process known as angiogenesis.
By adding a terminal sugar molecule, sialic acid, to glycoproteins such as mucin 5AC and Nectin2, it creates “a kind of camouflage,” Dr. Lakshmanan said. “These sugar-coated proteins interfere with immune surveillance, allowing tumors to grow unchecked.”
Dr. Lakshmanan refers to this interaction as a “glyco-immune checkpoint,” a novel concept inspired by existing immune checkpoint therapies.
In addition to immune evasion, the enzyme was found to play a role in nourishing tumor growth. “We observed a significant reduction in tumor progression and cell migration when we knocked down this enzyme in our lung cancer models,” Dr. Lakshmanan said. “That was a major finding.”
The group is now partnering with a biotech company in the Netherlands to test a drug that inhibits the sialic acid glycosylation driven by ST6GalNAc-I. “We’re exploring combination strategies using this drug alongside immunotherapy,” Dr. Lakshmanan said. “Our goal is to enhance the efficacy of existing treatments.”
The research was a multidisciplinary effort involving key collaborators, including Surinder Batra, PhD, Hartmann Chair in the UNMC Department of Biochemistry and Molecular Biology and director of translational research at the Fred & Pamela Buffett Cancer Center, and Apar Kishor Ganti, MD, associate director for clinical research at the Fred & Pamela Buffett Cancer Center. “Being able to work so closely with both clinicians and basic scientists has been invaluable,” Dr. Lakshmanan said.
The project began with RNA sequencing studies that highlighted ST6GalNAc-I as one of the most highly expressed genes in lung cancer tissue. Building on that discovery, Dr. Lakshmanan received a National Institutes of Health R21 grant. The team is now working to develop neutralizing antibodies that target ST6GalNAc-I modified glycoproteins.
If preclinical models continue to show promise, the therapy could move into clinical trials with support from Dr. Ganti’s clinical oncology team.
For Dr. Appadurai, UNMC’s collaborative environment has helped him grow as a researcher. “We’re given access to cutting-edge tools and mentorship,” he said. “It’s a great place to grow and contribute to patient-centered science.”
He expressed deep gratitude for his mentors and the collaborative environment at UNMC, noting the strong integration between basic science and clinical teams. Looking ahead, Dr. Appadurai said he plans to become an independent researcher, where he can continue contributing to cancer research and the development of new treatments.
Congratulations! Imay, Iniyan and team. Outstanding work!
Thanks Wasim
Super, congratulations.
Thanks Annan
Congratulations, Imaya, for such novel work of potentially great impact! Wishing you sustained success!
Dear Dr. Band
Thanks for your wonderful wishes.
Congrats Imay ! Rock on buddy.
Thanks Dr. Guru
Congratulation Imay. Great work!! Proud of you
Thanks Maneesh for your support
Thank you for this groundbreaking and important research. My husband died from lung cancer, so this is very near and dear to my heart. He was treated through Nebraska Medicine, and I will be forever grateful for the care he received. This type of research is one example of how important it is that the Federal Government continue to support research.
Excellent work. Thank you, again.
Thanks Lisa for sharing the experience and suggestions.
Thanks again
Big congratulations to Imay and the team on this exciting publication! Great to see your hard work and dedication being recognized. Wishing you many more impactful papers ahead! All the best!
Thanks Pals
Dear Dr. Lakshmanan:
Congratulation!
Best,
MF
Thanks Dr. Lin
Congratulations to the team!
Thanks Dr. Lin
Congratulations, Imay!
Thanks Madam
Congratulations Dr. Imay
Many -Many Congratulations Imay and Iniyan
Thanks Imran
Thanks Ranjana
Congratulations Imay and Iniyan!
Thanks Sarathy
Many congratulations to Iniyan and Imay.
Nice piece of study.
Thanks Sarathy
This is amazing! Congratulations!
Thanks
Congratulation Dr. Imay, Dr. Iniyan and the entire team
Dear Dr. Lakshmanan, CONGRATULATIONS!!
Well Deserved Recognition!!
Dear sir
Thank you very for your wishes
Hearty congratulations to Drs. Imay and Iniyan! Also, many congratulations to the entire team on this wonderful achievement!
Thanks Gopal
Congratulations Dr. Imay and Dr.Iniyan. Great to see your hard work and dedication being recognized.
Thanks Rajan sir
Congratulations, Imay and the team, for the great work!
Thanks Ashu for your contribution
Congratulations Imay and team!
Great work.
Thanks Sanjib for your contribution to this work
Congrats. Happy to be part of BMB.
Thanks
Great work, congratulations to Drs. Iniyan, Imay and all the authors.
Thanks Asad
Congratulations Iniyan and Imay !
So proud of Dr.Imay and Dr.Iniyan—this is a remarkable achievement and truly outstanding work. Wishing you continued success in all your future endeavors!
Thanks Nanda
Congratulations Imay and team. Very nice work. Lots of wishes for the next step.
Thanks Prasanta for your wonderful wishes
Congratulations on your valuable research and recent publication!
Thanks
Congratulations Drs. Imay and Iniyan. Your hard work paid off. Wishing you more success in your research ahead.
Thanks Saravanan for your wishes
Congratulations Iniyan and Imay and Team! Very interesting and looking forward.
Best wishes,
Thank you all for your wishes and support! I am deeply grateful to my mentors, Dr. Ganti, Dr. Lakshmanan, and Dr. Batra, for their intellectual guidance in advancing this exciting work. My sincere thanks to all my co-authors, including clinicians and basic scientists, for their invaluable contributions. A special thanks to Sarah Hankin for the interview and to UNMC News for sharing our story.
Congratulations Dr Imay, Dr. Iniyan and team, It is a Great Achievement
Great work! Congratulations!