A number of years back, there was a great deal of excitement about using viruses to target cancer. A number of viruses explode the cells that they've infected in order to spread to new ones. Engineering those viruses so that they could only grow in cancer cells would seem to provide a way of selectively killing these cells. And some preliminary tests were promising, showing massive tumors nearly disappearing.

But the results were inconsistent, and there were complications. The immune system would respond to the virus, limiting our ability to use it more than once. And some of the tumor killing seemed to be the result of the immune system, rather than the virus.

Now, some researchers have focused on the immune response, inducing it at the site of the tumor. And they do so by a remarkably simple method: injecting the tumor with the flu vaccine. As a bonus, the mice it was tested on were successfully immunized, too.

Revving up the immune system

This is one of those ideas that seems nuts but had so many earlier results pointing toward it working that it was really just a matter of time before someone tried it. To understand it, you have to overcome the idea that the immune system is always diffuse, composed of cells that wander the blood stream. Instead, immune cells organize at the sites of infections (or tumors), where they communicate with each other to both organize an attack and limit that attack so that healthy tissue isn't also targeted.

From this perspective, the immune system's inability to eliminate tumor cells isn't only the product of their similarities to healthy cells. It's also the product of the signaling networks that help restrain the immune system to prevent it from attacking normal cells. A number of recently developed drugs help release this self-imposed limit, winning their developers Nobel Prizes in the process. These drugs convert a "cold" immune response, dominated by signaling that shuts things down, into a "hot" one that is able to attack a tumor.

But not everyone has a response to these drugs, raising the question of whether there are other ways to activate the immune system at the site of a tumor. One potential option is simply the things that normally rev up the immune system: infectious agents. The immune response to cancer-targeting viruses mentioned above would provide an indication that this does occur. Others have targeted a variety of pathogens to the sites of tumors and found that this increases the immune response to the tumor as well.

To check whether something similar might be happening in humans, the researchers identified over 30,000 people being treated for lung cancer and found those who also received an influenza diagnosis. You might expect that the combination of the flu and cancer would be very difficult for those patients, but instead, they had lower mortality than the patients who didn't get the flu.

Moving to mice

For more detailed tests, the researchers moved to mice, using melanoma cells that can form tumors when transplanted into the lungs of the mice. These model systems often respond to treatments that don't end up working in humans, so the results have to be treated with appropriate caution. Still, they can be a valuable way of understanding the biology of the immune response here.

The use of melanoma cells is informative, as these cells cannot be infected by the influenza virus. So this system also provides a test of whether the tumor cells themselves have to be infected in order to increase the immune response to them. Apparently they do not. Having an active influenza virus infection reduced the ability of the melanoma cells to establish themselves in the lung. The effect isn't limited to the location of the infection, though, as tumors in the lung that wasn't infected were also inhibited. The effects were similar when breast cancer cells were placed into the lung, as well.

All of this is consistent with the immune stimulation provided by a pathogen. The stimulation causes a general activation of the immune system that releases it from limits on its activity that prevent it from attacking tumor cells. But does it require an actual infection? To find out, the researchers used a flu virus that had been inactivated by heat treatment. Normally, heat treating a virus is used to create a control for an effect that needs an active virus. But here, it turned out to be another experiment, as the heat-treated virus was also able to work just as effectively as the live virus.

This isn't entirely surprising, given that inactive viruses are often used as vaccines and thus clearly can stimulate the immune system. But that, in turn, suggested another experiment: would vaccines actually work? To find out, the researchers obtained this year's flu vaccine and injected it into the sites of tumors. Not only was tumor growth slowed, but the mice ended up immune to the flu virus.

Oddly, this wasn't true for every flu vaccine. Some vaccines contain chemicals that enhance the immune system's memory, promoting the formation of a long-term response to pathogens (called adjuvants). When a vaccine containing one of these chemicals was used, the immune system wasn't stimulated to limit the tumors' growth.

This suggests that it's less a matter of stimulating the immune system and more an issue of triggering it to attack immediately. But this is one of the things that will need to be sorted out with further study. The location of the stimulation will also need to be sorted out, too. Here, stimulation in one lung increases activity in both. But injection into muscles didn't work at all, and earlier work by some of the same team had indicated a heavy infection outside the lungs enhanced tumor growth by diverting immune cells elsewhere.

But the story does fit in well with the general consensus that the immune system can be a powerful tool against cancer, provided it can be mobilized properly. And, in at least some cases, a flu vaccine just might do the trick.

PNAS, 2019. DOI: 10.1073/pnas.1904022116 (About DOIs).