Scientists in Switzerland have discovered that a type of immune cell that normally helps to fight infection can actually work in favor of lung tumors, rather than against them.
Reporting their work in the journal Cell Reports, a team from the Ecole Polytechnique Federale de Lausanne (EPFL) discuss how the discovery may explain why many lung cancer patients do not respond to immunotherapy.
Lung cancer is the commonest cause of cancer-related death worldwide, accounting for nearly 1.7 cases out of 8.1 million in 2012.
After rising for several decades, rates of new cases of lung cancer are falling in the United States, in line with declining rates of cigarette smoking.
Nevertheless, lung cancer remains the second most common cancer in men and women in the U.S., where it is estimated to account for around 14 percent of new cancer cases and over a quarter of all cancer deaths.
The approach can slow the growth of cancer cells, stop them spreading, and increase the immune system’s ability to destroy them. There are several ways to do this, all using substances from the body or made in a laboratory to either boost the immune system or get a malfunctioning one to start working properly again.
In their study paper, the EPFL team explains how evidence gathered over the past 20 years shows that the ability of immune cells to penetrate solid tumors is a big factor in predicting outcomes for patients. This has encouraged investigation into cancer immunotherapy.
In the case of lung cancer, clinical trials of immunotherapy have “yielded promising results.” These therapies include drugs that target a pathway that the cancer uses to evade the immune system.
The pathway involves a protein called programmed death-ligand 1 (PD-L1) that sits on the surface of tumor cells.
When an immune T cell attempts to attack a lung cancer cell, its PD-L1 immobilizes it by binding itself to a protein called programmed cell death protein 1 (PD-1), which sits on the surface of the T cell.
This action triggers a whole series of reactions inside the T cells that stops them attacking the tumor cells.
However, despite attempts to shut down the PD-1/PD-L1 pathway as a way to “release the brakes on the immune system” and restore its ability to kill cancer cells, this has not been enough. The treatment still does not work for many lung cancer patients.
What is needed is a better understanding of the “immune compartment of lung tumors,” and the immune circuits that are active within it, the EPFL team writes.
“Indeed,” they continue, “considering the interplay between the different components of the tumor microenvironment and the carcinoma cells is essential to deciphering mechanisms driving cancer progression.”
It was this quest for further clarity that spurred the researchers — led by Prof. Etienne Meylan, who heads an EPFL laboratory investigating molecular mechanisms of lung cancer development — to carry out the study.
They genetically engineered mice to develop a form of lung cancer that is similar to one that arises in humans and then studied the various types of immune cell in and around the tumors that grew in the mice.
From this, they established an “immune signature” for lung cancer and found that a particular type of immune cell known as “Gr1+ neutrophils” contributed to disease progression.
The researchers then ran “depletion experiments” to find out what happens in tumors in which populations of neutrophils are substantially reduced.
They found that the absence of neutrophils completely altered the microenvironment in the immune compartment of lung tumors, allowing T cells to flood in.
From these and other tests, they found that neutrophils promote tumor growth, “prevent successful anti-PD1 immunotherapy,” and alter the function of tumors’ blood vessels.
By altering the function of a tumor’s blood vessels, the presence of neutrophils reduces the amount of oxygen present, which, in turn, promotes production of a protein called Snail that is known to help tumors to resist drugs, as well as to migrate and recur.
In addition, the team discovered that increasing production of Snail leads to an increase in another protein called Cxcl2, which promotes neutrophil penetration. This sets up a vicious cycle that speeds up disease progression.
“Since neutrophils are important in fighting pathogens, neutrophil depletion is unlikely to be used in the clinic. Instead, we must concentrate our efforts to understand exactly how neutrophils promote lung tumor development.”
Prof. Etienne Meylan