The study of cancer immunity has been a global challenge since William Coley first treated patients with his eponymous toxin in the late 19th century. As our understanding of the immune system has evolved, its role in the fight against cancer has become increasingly apparent. There have been some monumental milestones that helped shape cancer treatment as it stands today, including Steven Rosenberg’s trials of tumor-infiltrating lymphocytes in the 1980s, Hans Kolb’s cure of leukemia with donor T cells in the 1990s, and the discovery of checkpoint blockade, which led to Jim Allison’s recent Nobel Prize and the explosion of the field of immunotherapy.

The focus on immunotherapy puts us at risk for forgetting that the principal role of the immune system is tumor surveillance: the elimination of developing diseases before we are even aware of the danger. Cancer arises from the uncontrolled growth of tumor cells, which have evaded immune surveillance, and as such, immunotherapies are aimed at restoring the body’s natural anti-cancer responses. Nonetheless, despite some groundbreaking results, current immunotherapies remain effective in only a minority of patients.

The reason is that most such therapies only target one of two sides of the immune system; the adaptive response, and not the innate response. However, many immunotherapists are beginning to understand that broadening our therapeutic options to target the innate response as well, will give patients the best chance of beating their disease.

Adaptive immunity, also referred to as acquired immunity, is an antigen-specific immune response that can kill cancer cells and then generate an immunologic memory of each tumor-related antigen. This creates a reservoir of immune cells that are able to respond to cancer cells expressing the same specific antigen should it reappear. Adaptive immunity consists of T and B lymphocytes, which lyse tumor cells and generate antibodies to some of the tumor antigens. The process of adaptive immunity is the foundation of vaccinations such as the HPV-vaccine, which targets the virus responsible for most cases of cervical cancer.

Why is innate immunotherapy likely to improve outcomes? Innate immunity is our body’s first line of defense against infection and cancer. Around 10 percent of the lymphocytes in our peripheral bloodstream are part of the innate response, and 95 percent of those are natural killer (NK) cells. Each of these innate killer cells can recognize, target and kill harmful cells through recognition of proteins and glycoproteins, which are expressed on “stressed” cells, such as tumor and virally-infected cells.

In contrast to the adaptive immunity’s antigen-specific T cell responses, the innate system is relatively nonspecific and can provide a rapid response. While some of the earliest cellular immunotherapy trials in cancer were directed at innate immunity, many believed that the innate response is inadequate for the control of cancer and instead redirected therapies to focus on the T cell-mediated “adaptive” immunity.

Clinically, innate and adaptive immunity work together to protect us from infection and cancer, yet our understanding of innate immunity remains relatively poor compared to the adaptive responses. This is partly because adaptive immunity was not discovered until the 1970s, and partly because of the technical difficulties in studying NK cell biology compared to T and B cells. The importance of the innate response is accepted in invertebrates, which lack adaptive immunity, but it is clearly essential for humans too.

Human NK cells are evolutionarily conserved and even share many molecules with NK cells from invertebrates such as leeches and sea urchins. From the early days of HIV infection, we saw that patients with a fundamentally damaged adaptive immune system were still protected by their innate immune system and only succumbed to some intracellular bacterial infections and rare tumors. They did not die from common infections or uncontrolled tumors.

Today, we have a great deal of supporting evidence for the importance of NK cells and the innate response in protection from cancer. Cancer cells are constantly arising in our bodies as a consequence of random genetic mutations, some of which give a cell a survival or proliferation advantage. These random changes are mostly novel and have never been presented to the adaptive immune system. The only cells able to detect the “stress” signals of a tumor cell that is dividing too frequently are NK cells, which can eliminate tumor cells before they become a clinically detectable cancer.

A Japanese study published in 2000 measured the resting NK cell response to a single cancer cell line in over 3,500 healthy people on a single day of their life, and then followed them all for over 11 years. Those with the weakest resting NK cell function on the single day that they were tested had a statistically significantly increased incidence of succumbing to any form of cancer over the period of follow-up. The importance of innate immune surveillance is also seen in NK cell–deficient mice, which generate malignant lymphomas spontaneously.

Far from being the poor, unsophisticated relative of the adaptive immune response, innate immunity is central to survival. As we increase our understanding of the innate immune response and discover how to best manipulate it, we will see even greater advances in immunotherapy of cancer with NK cell therapies alone, and alongside those of the adaptive immune response, to target cancer better than ever before.