The Power of Scientific Partnership

Teamwork and time, along with funding, are three of the most important factors driving new scientific discoveries. As we learn more about human health and disease, researchers need to ask increasingly complex questions to further our understanding of what causes diseases like pancreatic cancer and how to design treatments to address them. Biomedical research increasingly employs specialized techniques and expertise to properly evaluate new ideas and vet new therapies. Complex studies need to be designed and executed and with advanced technology, the vast amount of data that can be generated takes time to properly analyze and interpret. Teamwork with collaborators is key for driving new ideas forward and for the expertise to employ multiple techniques to thoroughly evaluate any one hypothesis. Collaborators bring their own curiosity, questions, and voice to tackle these ever-evolving questions. A recent paper published in the journal Immunity, “Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumor microenvironment” is an example of this type of effort.

Before she was a 2024 Hirshberg Foundation Seed Grant recipient, Katelyn Byrne, PhD, was an Instructor in Medicine at University of Pennsylvania and a 2016 Parker Fellow for the Parker Institute for Cancer Immunotherapy (PICI). There, she evaluated the impact of activating the immune system to reject pancreatic tumors in preclinical models in the lab of Robert Vonderheide, MD, PhD. After presenting her work at a PICI retreat, she was approached by Ron Germaine, MD, PhD from the National Institute of Health (NIH). This led to an invitation to speak at the NIH and the idea for a collaborative project between Dr. Byrne and Dr. Germain’s lab. Vivien Maltez, PhD was a postdoctoral fellow in Dr. Germaine’s lab at the time and became Dr. Byrne’s counterpart in the project.

Both women studied immunology during their PhD studies. At Dartmouth, in the lab of Mar Jo Turk, PhD, Dr. Byrne studied autoimmunity and how it could relate to cancer immunology, showing how memory T cells that developed in people with melanoma enhanced the autoimmune disorder vitiligo. Dr. Maltez studied innate immunity and host-pathogen interactions at UNC Chapel Hill. It was in their respective post-doctoral positions, Dr. Byrne at UPENN and Dr. Maltez at the NIH, that they turned their attention to immunotherapy in pancreatic cancer.

Immunotherapy, a type of treatment aimed at engaging the immune system to attack and kill cancer cells, has had success and redefined care in multiple types of cancer, including melanoma and lung cancer, but has little effect in pancreatic ductal adenocarcinoma (PDAC). Understanding why PDAC tumors don’t respond to immunotherapy can lead to opportunities to reverse generate better outcomes for PDAC patients. The immune system is made up of many cell types with T cells being the main target for current immunotherapy approaches. There are multiple types of T cells; effector T cells that identify and kill infected or tumor cells and regulatory T cells (Tregs) that suppress the immune system from becoming overactive and causing damage. The most successful type of immunotherapy is checkpoint inhibition which blocks proteins on effector T cells that stop their ability to kill tumor cells. Blocking these proteins results in an anti-tumor immune response and can lead to tumor regression in some types of cancer.

In their recent Immunity paper, led by Dr. Byrne, Dr. Maltez, and Dr. Germain, the team found that one reason PDAC tumors are resistant to checkpoint inhibition is due to the large number of Tregs in the tumor microenvironment (TME). The balance of effector T cells and Tregs is vitally important for maintaining the ability to fight disease without developing autoimmunity. When there is a large number of Tregs in the TME, checkpoint inhibition cannot overcome the Tregs’ suppressive forces to initiate an anti-tumor response.

Using models of PDAC, the team evaluated an experimental therapy called agonistic anti-CD40, an antibody that activates a molecule called CD40. Treatment with agonistic anti-CD40 lead to an increased number of effector T cells and a decreased number of Tregs in the TME. They showed that the reduction of Tregs was caused by the transformation of these cells from Tregs to cells that behaved like effector T cells and called these cells ExTregs. Additionally, when agonistic anti-CD40 was combined with checkpoint inhibition, both effector T cells and ExTregs become activated and engaged in an anti-tumor response, effectively reversing resistance to checkpoint inhibition.

The designing, execution, and interpretation of these studies was a lengthy endeavor that spanned the COVID pandemic and the women moving on to start their own laboratories. In 2022, Dr. Byrne became an Assistant Professor of Cell, Developmental, and Cancer Biology at Oregon Health & Science University (OHSU) School of Medicine. In 2024, Dr. Maltez became an Assistant Professor in the Division of Allergy, Immunology, and Rheumatology at University of California, San Diego and in 2025 received a Hirshberg Foundation Seed Grant award.