If you had asked most people in 2019 about it, they would have probably not been too interested in immunity. But as it did to so many other things, the pandemic changed that. In 2021, immunity is a hot topic – and it was also a hot topic at LINO70, where it was discussed in depth by two Nobel Laureates: Jules A. Hoffmann and Tasuku Honjo.
The problem with immunity (or rather, one of the problems with it) is that it’s a complex and multi-layered response. It’s not a silver bullet or a one-size-fits-all approach. Various organisms employ various responses against pathogens, and the processes behind those responses are still not fully understood, but we’re getting there. In 2011, Hoffmann was awarded the Nobel Prize for his discoveries on the activation of innate immunity. At an Agora Talk, Hoffmann discussed his findings and what other interesting things are going on in this field.
Insects and Innate Immunity
In a brief introduction, renowned German immunologist Stefan Kaufmann noted that through Hoffmann’s work, we know that “the innate immune system can and does scan the body for foreign invaders and independently, adjusts to the type of foreign invader – viruses, parasites and so on – and then can initiate a strong, effective response. Moreover, we now also know that, in this way, innate immunity instructs acquired immunity.”
The innate immune system is one of two main immunity strategies found in vertebrates, the other being adaptive (or acquired) immunity. It’s also the older of the two, but it’s not as rudimentary as was once thought. “Innate immunity was essentially understood as phagocytosis – taking up cells and demolishing them,” Hoffmann explained. But there is much more to innate immunity than researchers had realised a century ago. Hoffmann was awarded the Nobel prize for his work on the Toll gene in innate immunity, but he has been studying innate immunity for decades. “We showed that innate immunity is present in all animal forms,” he mentions.
It makes sense for innate immunity to exist in all creatures. After all, vertebrates only developed adaptive immune systems some 400-500 million years ago. “Innate immunity appeared at least one billion years earlier, and maybe even earlier, but that’s difficult to ascertain now,” Hoffmann mentions.
Much of Hoffmann’s work was carried out on insects. This may seem surprising at first glance but is actually very relevant. Invertebrates represent 95 percent of all species on Earth now, and insects alone represent around 80 percent of all living species. Insects are also very resilient to a number of different pathogens. Insects are attacked by fungi, bacteria, viruses, protozoa, and so on; and, as Hoffmann explained, they are remarkably resistant to these infections. In fact, it’s exactly because they are so resistant that they are such important disease vectors.
“They put one third of humanity at risk of microbial infection via those vector capacities. The current estimates are that one billion people are affected every year.”
“So we knew that this very large group has a strong immune defense – but we did not know when I started my thesis the mechanisms of this.”
Over the years, it became apparent that innate immunity is much more complex and multifaceted, and unexpected findings came up. For instance, Hoffmann notes that the main enemies of bacteria are other bacteria – and bacteria deploy antibacterial peptides to counteract each other. This is not just an interesting story but can be useful for us to find antibacterial defenses.
From Hoffman’s research and down to the ongoing pandemic, we’ve kept on learning more and more about how our immune systems help fight pathogens. But the interactions of the immune system with the rest of the human body go far beyond just pathogens. As Tasuku Honjo explained in a separate lecture, it even has a lot to do with cancer.
The Serendipities of Immunity
In 1992, Honjo and his colleagues came across a molecule called programmed cell death protein 1 (PD-1) and then showed that this molecule functions as a braking system in acquired immunity. Essentially PD-1 helps keep the immune system in check and can suppress T-cell inflammatory activity. This is excellent for preventing autoimmune diseases, but it can also stop the immune system from killing cancer cells. Too much PD-1 and the immune system won’t do its job properly; too much of it, and you run the risk of autoimmune disease.
Things progressed steadily in the following years. In 2002, Honjo and colleagues showed that blocking PD-1 in mice models can cure tumors by reactivating acquired immunity. Then, in a landmark moment in 2014, the treatment of cancer in humans by PD-1 blockade was approved by regulatory bodies in Japan and the USA.
Essentially, we have a novel way of treating some types of cancer through acquired immunity, essentially using the same mechanism applied to infectious diseases against cancer.
Things haven’t stopped since 2014, either. There are over 1,000 clinical trials ongoing, the method seems effective against numerous types of tumors, and the effect seems to be long-lasting.
“When you stop the treatment, the effect still continues,” Honjo explains.
The Future Looks Bright
Cancer won’t be eradicated anytime soon, Honjo believes. But it could be kept well under control by 2050. It’s remarkable to even think that it could be less than three decades before we start controlling the dreaded disease, but given the speed at which PD-1 treatments are progressing, it’s possible, Honjo believes. There’s one big catch, however.
“We can block the tumor growth in young mice, but not in aging mice,” Honjo states. In a simple and elegant experiment, it was shown that older mice are far less responsive to the therapy than their younger counterparts. Surprisingly, experiments like this are rare, especially because older mice are more expensive, Honjo notes. But if we want to get the true idea of what’s happening, older mice are essential – because older people are more likely to develop tumors.
“Most people don’t keep mice that long, it’s actually very expensive. I think that could be the major reason why people don’t work on the mice. […] But it’s mostly aged people who get cancers, so we have to work on aged animals to see reality.”
Honjo is optimistic for future therapies and believes we’re only now starting to see the potential this method can offer. For the young researchers in related fields, there’s plenty of room to find new things. “Immunotherapy is just beginning,” he concluded. “There must be an enormous possibility for clinical application.”