FEATURE ARTICLE
Healing Heat: Harnessing Infection to Fight Cancer
Modern immunology plus historic experiments suggest a better way to gear up the human immune system to battle malignant disease
Uwe Hobohm
Harnessing Immunity
It is not true, as Coley believed of S. pyogenes, that all these pathogens produce some cagey anti-cancerous substance. Even malaria was reported in the case histories—a disease caused by plasmodia rather than a virus or bacterium. It’s unlikely that pathogens of such disparate evolutionary roots could produce the same cancer fighter. Much more likely is that the sequence of immune reactions triggered by the infections was the same.
The immune system is capable of finding a malignant cell, just as it is able to localize a bacterium, a virus, a worm or a malaria plasmodium. As early as 1956, scientists observed that the survival rates of gastric cancer patients correlated with the number of a specific type of immune cell observed in and around their tumors. The more tumor infiltrating lymphocytes (TIL), the better. Still, millions of people die from cancer each year. Why?
Barriers must exist to prevent an organism’s immune system from attacking its own tissue. Otherwise, devastating autoimmune diseases would be more common. Mammalian immune systems are structured to maintain a delicate balance between recognition and removal of pathogens and not attacking “self.” Bacteria and viruses are invaders that the immune system generally is poised to attack. Malignant cells, derived from native cells, don’t generate the same reaction since they are “self”—at least that was the long held explanation.
Cancer cells can carry hundreds of mutations that distinguish them from healthy cells. But the immune system often remains in an “observer” state in their presence rather than engaging in battle as it does against bacterial or viral infections. The reason for this incomplete immune response is a long-standing puzzle in cancer immunology. William Coley’s experiments may help today’s scientists solve it.
The human immune system can be broadly divided into two parts, the innate and the adaptive. The older, innate immune system reacts within minutes after invading pathogens are encountered. The adaptive system, which employs evolutionarily younger and more customized tools, takes longer to generate specialized antibodies and T cells to attack threats.
A look into vaccinology illustrates why involvement of the innate system may be crucial. Ordinary vaccines such as those against measles, smallpox, tuberculosis or whooping cough either contain “attenuated” live pathogens, sterilized pathogens or pathogenic antigens. These components are geared toward the adaptive immune system; they lead to the production of pathogen-specific antibodies or T cells.
But all vaccines contain another component, so-called adjuvants. For decades nobody understood why adjuvants enhance the immune reaction. The immunologist Charles Janeway called adjuvants “doctors’ dirty little secret.” Today we know that adjuvants stimulate the underestimated portion of the immune system, the innate arm. Some vaccines would be almost useless without an adjuvant.
Evolution wired both arms of our immune response to work together. A defective innate system allows pathogens to attack more rapidly, putting the slower adaptive system at risk of being overrun. For too long, the attention in cancer immunology was focused on the adaptive part of the immune system alone. Only in recent years have cancer immunologists turned their attention to understanding the role of the innate system.
Scientists have expanded the observation from the 1950s that a high number of lymphocytes near gastric tumor tissue improves patient survival. The same pattern has been found in more than 3,400 patients with cancer of the breast, bladder, colon, prostate, ovary, rectum and brain. In the case of breast cancer, the difference was striking. Patients with high numbers of TIL had a six-year survival rate of more than 60 percent, whereas no patients with very low numbers survived. P. H. Cugnenc et al. observed in 2006 that the location and density of T cells within colorectal tumors is a better predictor of patient survival than tumor classification by size and spread. This is a profound observation, since it proves that the immune system can constrain cancer, at least for a while.
In these cases, presumably, constant elimination of some malignant tissue takes place, although not complete eradication. At the same time tumor cells evolve due to their inherent genetic instability. They produce variants leading to successive cell populations with different immunogenicity—different vulnerability. Thus, while one variant cell is detected and destroyed, another variant develops for which the immune system has to generate novel bullets. The outcome is often fatal.
Dendritic cells, which link the innate and adaptive immune systems, likely are hugely important players in restraining cancer. Dendritic cells act like patrolling sentries, prowling boundaries between the body and the outer world on and under skin, within the epidermis and within mucous membranes in the mouth, nose, ear and colon. These cells ingest pathogens and cell debris and produce from them structures known as antigens—biological fingerprints that stimulate T cells and B cells to customize their immune attacks. Dendritic cells carry those antigens to lymph nodes and display them on their surfaces to T cells, key actors in the molecular chain that launches adaptive immune attacks.
There is one important requirement in this scenario that has not been recognized until recently. Dendritic cells need so-called danger signals to become maximally activated. Cancer cells do not produce the right signals to activate them; but certain classes of bacterial and viral components do. They are called pathogen-associated molecular patterns (PAMP).
PAMP is the name for a collection of chemically diverse substances found in parts of biological invaders such as the lipopolysaccaride in bacterial cell walls or the flagellin in bacterial propellers. PAMP also includes double-stranded RNA found in viruses and parts of infectious fungi, such as mannan or zymosan. They bind to the same protein family in the human body as do adjuvants in vaccines: so-called Toll-like receptors (TLR), which dendritic cells employ. No other class of substances is known to induce maturation of dendritic cells as efficiently as PAMP. That ability may explain how bacterial infection, in the presence of fever, can mobilize immune attacks against cancer.
The details of this hypothesized cross-immune stimulation are not yet known. But a hint may be distilled from an experiment published in 2004. Cancers are known to tone down immune responses. They produce and release immune-suppressing signals into their environment, phenomena called tumor escape or tumor tolerance induction. Drew Pardoll at Johns Hopkins University and colleagues wanted to break this tolerance and revitalize a normal immune response against an established tumor in mice. His group administered dendritic cells plus tumor antigen, but tolerance for the antigen remained.
In a second experiment, dendritic cells were infected with a virus. That time, tolerance for the cancer antigen was broken and the immune system, pushed into a higher gear, launched a full attack. This makes sense. Viruses produce PAMP. Dendritic cells are fully activated with help from PAMP.
This suggests an explanation for Coley’s success with some of his patients and for those documented spontaneous cancer remissions after fevers. Dendritic cells ingest both pathogens and dying cells and eventually display antigens needed to activate T cells, probably by displaying both on their surface. And it’s likely that fever has an important role in this scenario. As Klemens Trieb and colleagues reported back in 1994, cancer cells can be more vulnerable to heat than normal cells. Fever produces heat, so it is fair to argue that fever may produce an unusually high amount of cell debris from cancer cells, possibly resulting in potentially more cancer-cell antigens being collected by dendritic cells. The immune system requires a certain amount of antigen for full activation; low antigen levels are ignored.
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