Where Cancer-killing T-cells Come From

New research published today in Nature Medicine by scientists from the Stanford University School of Medicine and the Parker Institute for Cancer Immunotherapy sheds new light on the origins of tumor-fighting immune cells following immunotherapy treatment with anti-PD-1 checkpoint inhibitors.

Using single-cell RNA sequencing technology, the group discovered that T-cells homing in on cancer did not appear to come from tumors as previously suspected.

“The big surprise is that the T-cells sitting in the tumor before the start of checkpoint inhibition treatment are inert,” said senior author Howard Y. Chang, MD, PhD, a PICI member investigator and professor of dermatology and genetics at Stanford. “The vast majority of the tumor-specific T-cells that are proliferating come from outside the tumor.”

Giving a patient anti-PD-1 checkpoint therapy apparently drives these T-cells to move in and clone themselves into a cancer-killing army, Chang said, partially explaining how the immunotherapy treatment boosts the immune system’s ability to destroy tumors.

A new anti-PD-1 paradigm

The findings upend the prevailing theory about how anti-PD-1 drugs affect the immune system, according to co-first author Ansuman Satpathy, MD, PhD, a Parker Bridge Scholar and assistant professor of pathology at Stanford.

A common belief is that anti-PD-1 works by activating or reinvigorating T-cells that are already in the tumor.

“It might, but our findings show that anti-PD-1 therapy also recruits cancer-killing T-cells from somewhere else,” Satpathy said. “You’re recruiting a whole new arsenal of cells to fight the tumor.”

If confirmed, the research has implications for cancer immunotherapy drug development, which is largely focused on T-cells near or inside of a tumor.

“A tremendous amount of effort has gone into profiling tumor infiltrating T-cells before and during immunotherapy treatment,” said Samantha Bucktrout, PhD, one of PICI’s directors of research and a co-author on the paper. “But perhaps broadening the focus to other cell types will likely bring more progress.”

Paving the path for blood-based biomarkers

The team found this army of cancer-killing T-cells in an unexpected place: the bloodstream.

That finding opens up the possibility of developing a blood test that could help determine whether a patient might respond to immunotherapy. Currently, immunotherapies such as checkpoint inhibitors work for 20 to 30 percent of patients.

A blood-based biomarker test that could predict whether immunotherapy would be successful would be a game-changer, and potentially easier and quicker to perform than a biopsy.

“Most biomarkers of interest have been based on factors you would measure at the tumor site,” said co-author Daniel Wells, PhD, PICI’s senior data scientist. “This supports the idea that biomarkers in blood are going to be important as well.”

The research was one of the first fruitful collaborations between PICI scientists, Satpathy and Chang.

Prior to this project, Chang’s lab – more known for groundbreaking work in epigenetics and RNA biology – had not focused on immunotherapy. Collaborating on the research with PICI provided him an opportunity to apply single-cell technology to the study of cancer immunology, Chang said.

“We benefited tremendously from collaborating with Danny Wells, Samantha Bucktrout and other scientists at PICI central, who helped us with computational methods to track T-cell specificity and T-cell clones.”

Seed for collaboration planted at PICI scientific retreat

Like many PICI projects, the collaboration that led to the paper originated at a PICI retreat, which in atmosphere feel like part scientific conference, part family reunion.

At the spring 2018 retreat, Wells saw Chang present some exciting early data during one of the marathon scientific sessions. At any given time, they include luminaries of the field such as PICI directors Jim Allison, PhD, of MD Anderson Cancer Center, and Carl June, MD, of the University Pennsylvania.

Afterward, Wells approached Satpathy, a former post-doc of Chang’s who now runs his own lab at Stanford with funding from PICI. They talked into the wee hours, laying the groundwork for exploring data generated by Chang, Satpathy and Chang’s doctoral student, Katie Yost.

“We were like, yeah. Let’s make this happen!” Wells said.

The group worked collaboratively for months, with Yost taking on the role of lead author. Other collaborators brought onto the project included PICI data engineer Robin Kageyama, PhD, and Mark Davis, PhD, a co-director of PICI at Stanford and professor of microbiology and immunology who pioneered the methods used to track T-cells.

The outcome – a collaborative research paper in Nature Medicine that brings to light a paradigm-changing finding – is classic PICI, Bucktrout said.

“The retreats and PICI’s whole way of operating foster a kind of deep connection and intellectual cross-pollination among the best minds, across many different fields. It’s something that’s not really found or even possible in other settings,” Bucktrout said. “It’s a central reason why PICI is a transformative force in immunotherapy.”