By William Chambers, PhD
Earlier this month, 3 immunologists were awarded the Nobel Prize for Medicine and Physiology. Two of the 3, Bruce Beutler and Ralph Steinman, are former research grantees of the American Cancer Society, bringing the total of Nobel Prize winners who are former grantees to 46. Drs. Beutler and Jules Hoffman, the third awardee, were singled out for their work on non-adaptive immunity, and Dr. Steinman was recognized for his discovery of dendritic cells, which are singularly important in adaptive immunity. So why is their work important, and what does it have to do with the fight against cancer?
The immune system
The body's defense, or immune system, is composed of both a non-adaptive response and an adaptive response. Both work to protect the body, but the non-adaptive immune system is less sophisticated or less highly evolved than the adaptive immune system.
Non-adaptive immunity is seen in living things that aren't as complex as humans, such as sea urchins or worms. In these creatures, cells called phagocytes recognize, ingest, and destroy invading organisms. Those cells can also release chemical substances that help protect the animal. Phagocytes are also part of the non-adaptive immune system in humans.
Beutler and Hoffman's work
Drs. Beutler and Hoffman won the Nobel Prize for identifying a set of receptors on immune cells, including phagocytes, that allowed those cells to recognize invading bacteria, and for showing which molecules on the bacteria were recognized. Those receptors are called Toll-like receptors, or TLRs. We now know that there are at least 13 TLRs and that they are expressed on a number of types of immune cells.
The understanding of how non-adaptive immune cells recognize infectious agents has been profoundly important in many ways, and has also resulted in the current study of many potential therapies for cancer using compounds that stimulate cells through TLRs. Agents such as imiquimod, which stimulate cells through TLR7, have been approved for treating basal cell carcinoma. Other agents such as Monophosphoryl Lipid A, which stimulates through TLR4, are being tested for use on a variety of cancers.
Adaptive immunity is what most of us think about when we are protected from infections by getting vaccinated. Vaccines work by creating a long-lasting protective immune response that is highly specific to a particular bacteria, virus, or other invader. When you receive a vaccine, your adaptive immune system learns to recognize and attack the invader any time you are exposed to it. This response becomes faster and stronger with each subsequent exposure.
Dr. Steinman identified an unusual looking cell which he called a dendritic cell, and showed that it belonged to the immune system. He then showed that dendritic cells help other immune cells recognize and destroy bacteria, viruses, or tumors. Dendritic cells are the most efficient at this task, and have now become part and parcel of many, many vaccines used to induce specific immunity, particularly against cancer.
In 2010, the FDA approved the first therapeutic anti-tumor vaccine, called Provenge/Sipuleucel-T, for advanced prostate cancer. This vaccine uses a patient's dendritic cells to stimulate an adaptive response to attack his prostate cancer.
Promise for future advances
The immune system must be capable of protecting us from an infinite variety of diseases, and from any form into which the disease- causing agents evolve. Looking at it from that point of view, it is not surprising that the immune system is highly complex and flexible.
The work of Drs. Beutler, Hoffman, and Steinman helps us understand that both non-adaptive and adaptive responses must work together, and are in fact dependent on each other to work. For instance, we now know that some of the TLRs described by Drs. Beutler and Hoffman that are part of the non-adaptive immune response are also present on dendritic cells, a key part of the adaptive immune response. To take this full circle, many scientists are now investigating the use of compounds that stimulate TLRs in combination with vaccines using dendritic cells as a means of treating cancer. For instance, CpG, which stimulates dendritic cells via TLR9, is being investigated for use to strengthen immune responses to melanoma and prostate cancer vaccines, among others.
The work of these newly-named Nobel Prize laureates will undoubtedly have a major impact as we study how to better prevent and treat cancer. We are proud to have funded them and to recognize their contribution to the fight against cancer.
Dr. Chambers is director of clinical cancer research and immunology for the American Cancer Society.