The UCSF researchers, led by first co-authors Alexis Combes, PhD, and Bushra Samad, MS, and senior author, Max Krummel, PhD, obtained tumour specimens from 78 UCSF clinicians, and surveyed 364 tumours biopsies from patients and categorised them into groups based on their immune microenvironment.

Their findings, published in the journal Cell, offer a new way of looking at cancer immunotherapy that matches the immune environment around the tumour and points the way to personalised immunotherapies.

“This is a new framework for how to look at cancer patients,” said Combes, director of the  D2B CoLab and incoming assistant professor in the Department of pathology at UCSF.

“This work will help clinicians find the right biology to target and avoid targeting cells that aren’t present in the tumour.”

Immunotherapy for cancer treatment harnesses the body’s immune system to fight cancer. It has held great promise since it was first developed as a biological therapy used to treat a variety of cancers.

While it has proven successful for some patients, immunotherapy does not work for all patients.

“We were driven by this question of why immunotherapies work for some people and not others,” said Krummel, Robert E. Smith Endowed Chair in Experimental Pathology and director of the Krummel Lab at UCSF. “It’s more complex than responders and non-responders. Our goal was to discern how many responses there are to these targeted therapies.” 

Tumours have microenvironments

Tumours are more than just out-of-control cells.

They are also filled with immune cells which are supposed to kill the cancer cells.

But in cancer, malignant cells are able to overcome the body’s immune response and continue to multiply. 

The research team found that a variety of cancers come in prescribed forms, each of which represents a unique subversion of the body’s immune defences.

The researchers characterised different microenvironments in the tumours, looking at which immune cells were present and which genes were expressed. 

“We could see that the tumours and their environments inform each other,” said Combes.

The research team was able to group the tumours into 12 groups, which they call archetypes.

To their surprise, the tumours contained a wide range of immune cells, such as macrophages, NK and B cells -- beyond the T cells which are the focus of current immunotherapies. 

Their research indicates that the immune archetype of a tumour is not necessarily tied to a type of cancer. 

Some archetypes are largely drawn from just a few kinds of cancer.

Others draw from many.

This means that some melanomas are quite similar to some lung tumours but more biologically different than other melanomas. 

“Unbiased interrogation of multiple data sources including genetic sequencing, cell surface markers, imaging, and patient clinical data, set the groundwork atop which we were able to identify and describe these immune archetypes,” said Samad.

Identifying patients for clinical trials

The classification scheme not only identifies which tumours are likely to be vulnerable to current immunotherapies, it also helps identify which patients might be most responsive in which clinical trial. 

“This framework allows us to eliminate a bunch of noise,” said Krummel. “We may have been targeting cells that weren’t even in the tumour.”

Clinicians and researchers contribute knowledge

Krummel’s research team was able to bring together a large group of UCSF researchers and clinicians - 78 in all - who lent expertise across disciplines. 

The authors came together with the common goal of better leveraging promising therapies. This dual viewpoint and large body of knowledge is an approach being fostered by UCSF’s CoLabs.

"This is just the beginning of this project,” said Krummel. "We believe this is the next step in personalised medicine for cancer therapy. When the immunotherapy you design can thus be placed against the correct biology. That biology may not always go by a name we’ve heretofore known. Archetypes, we think, are those names.”

Source: University of California - San Francisco