By Mimi Yuejun Guo
Forty years on, it remains a foundational discovery in cancer science.
The T-cell receptor (TCR) discovery in 1984 was groundbreaking, paving the way for revolutionary immunotherapies, offering new hope to cancer patients around the world and continuing to spark innovative treatments.
The seminal work of Dr. Tak Mak from UHN's Princess Margaret Cancer Centre and Dr. Mark Davis of Stanford University identified the genes encoding TCR for humans and mice, respectively.
As research in this field continues to advance, the potential to harness the power of the immune system to fight cancer more effectively is a beacon of hope for patients and their families.
"This discovery enabled us to understand how T cells develop and how autoimmune diseases develop and the fundamental principles underlying T cell activation," Dr. Pamela Ohashi, Senior Scientist at the Princess Margaret, said in the opening remarks at the 40th Anniversary T-Cell Receptor Symposium.
"It had a profound impact on cancer treatment, as tumour-specific T-cell receptors now guide immune responses to target and destroy tumours through various innovative approaches," said Dr. Ohashi, a pioneering researcher in her own work helping to advance immunotherapy as a treatment to fight cancer.
To celebrate the milestone, UHN and University of Toronto proudly hosted the symposium of global researchers, including Drs. Mak and Davis, as well as Nobel laureate James Allison, who received the honour in 2018 for the discovery of immune checkpoint blockade therapies.
Looking back on the health transformation driven by the TCR discovery, Dr. Mak paid tribute to the many collaborators and teams he has had over the years.
"We are humbled and grateful that our contributions to the discovery of the TCR and its biology in health and disease have had such a significant impact," he said. "We look forward to future advances in the basic science of TCRs from our lab and from others, and also to bolster the case and the tools for the therapeutic use of this amazing receptor."
Dr. Naoto Hirano, Chair of Immuno-Oncology Program at Princess Margaret Cancer Centre, said he was inspired to pursue a research career in Toronto thanks to Dr. Mak and his remarkable legacy.
"The TCR discovery laid the foundation for the development of modern cancer immunotherapies, including Chimeric Antigen Receptor (CAR)-T and TCR-T cell therapies, as well as immune checkpoint blockade therapies," he said.
"The molecular techniques he introduced sparked my interest in using immunology to tackle medical challenges," recalls Dr. Hirano. "His contributions continue to influence my research in T cell-based immunotherapies, not only in cancer but extending beyond it."
In the late 1970s, scientists understood that T cells express some form of cell surface receptor that is involved in antigen recognition. However, very little was known about the generation of T cell specificity and diversity, creating an urgent need to understand the structural and genetic basis of TCR.
Both Drs. Mak and Davis and their teams created collections of T cell specific cDNA. Dr. Yusuke Yanagi, a postdoctoral researcher at Dr. Mak's group at the time, reported that they found a unique DNA sequence from human T cells, encoding the information to produce a protein that has a molecular weight of 30 kilodalton.
The protein had structural features that allowed it to be anchored on the cell membrane, with the major part exterior to the cell, which was later determined to be the beta chain of the TCR.
These pioneering findings allowed characterization of the TCR to be completed rapidly and paved the way for subsequent discoveries on other structural components of TCR, which led to our current comprehension of the TCR complex as an eight-part receptor with intricate signaling pathways and functions.
Transforming cancer care
By engineering TCRs to recognize tumour-specific surface proteins, T cells can be directed to target and kill cancer cells. This type of therapy, known as CAR-T therapy, was developed through the efforts of many immunologists and cell therapists, including Drs. Michel Sadelain and Carl June. Their talks at the symposium deconstructed CAR-T therapy and provided an informed history of its inception and development.
While TCRs are crucial for initiating T cells' immune response, other molecules on the surface of T cells can work as a "brake," or an immune checkpoint that helps the body prevent overreaction in immune responses.
In 1995, Dr. Paul Waterhouse, working in Dr. Mak's lab at Princess Margaret Cancer Centre, became the first in the world to discover that a gene called CTLA-4 is the brake on the T cell function.
In 1996, Dr. James Allison at the University of Texas MD Anderson Cancer Centre developed the world's first antibody to block CTLA-4's "braking" action, freeing T cells to attack cancer. In 2018, he received the Nobel prize for his work, which built significantly on the discoveries of the Princess Margaret researchers.
At the symposium, Dr. Allison noted the dramatic improvement in cancer patient survival thanks to immunotherapy.
"Today, 50 per cent of metastatic melanoma patients treated with immunotherapy are in remission nine years out and counting," he said "In 2011, it was just seven months."
"Melanoma has gone from an incredibly lethal disease to a disease with much better outcome. As we learn more about how this works, we can get response rates even higher for melanoma and other cancers."
