Vol. 04 Issue 3, Early Fall 1999
Edward J. Pearce, Associate Professor of Parasitology
College of Veterinary Medicine, Cornell University The Immune Response: A System for Fighting Infection
The immune system evolved to respond in an aggressive but controlled way to dangerous infectious organisms (pathogens). The essence of the response is that components of an innate defense system identify invading pathogens such as bacteria, viruses, fungi and parasites as foreign and establish an environment in which immune cells known as lymphocytes can respond specifically to distinct molecular components (called antigens) of the pathogen and thereby target the pathogen itself for destruction. Sometimes the innate defense system succeeds in halting the invasion before there is any real need for the lymphocytes to be involved, but usually exposure to a pathogen results in a lymphocyte response.
The Immune Response and Cancer
In contrast to pathogens, which are molecularly distinct from the host (the individual harboring the infection or tumor), cells which have become cancerous due to exposure to physical or chemical carcinogens share the great majority of their molecular components with all other cells in the host's body. This presents the first of several major problems faced by the immune system when faced with a cancer - the dangerous tissue is difficult to distinguish from normal tissue. Perhaps most importantly the cancerous cells are unlikely to activate the innate defenses which rely heavily on major differences between pathogen and host to recognize the invading organism. Without an appropriately activated innate system, it is difficult to recruit and activate the lymphocytes, which themselves do possess the ability to recognize the subtle differences between cancerous cells and normal cells. Thus, the immune system seems to play little role in preventing the growth of most cancers. This is clearly illustrated by the fact that common forms of cancer, including breast cancer, do not occur at higher frequency in people with AIDS or other immunodeficiency diseases. On the other hand, cancers associated with viral infections, such as Kaposi's sarcoma and cervical cancer, do occur more commonly in people with immunodeficiencies, reinforcing the role of the immune system in dealing with diseases with an infectious component. Paradoxically, prolonged immune system-promoted inflammation associated with certain chronic infections is also thought to play a role in promoting cancer. Nevertheless, the fact that the prevalence of breast cancer does not differ in immunodeficient versus immunologically responsive individuals can be taken as evidence that: 1) the immune system is not playing a major role in either protecting against or promoting breast cancer, and 2) that there is not an underlying role for an infectious pathogen in this common malignancy.
Vaccination Against Cancer
While the data from studies of breast cancer prevalence in immunodeficient individuals argue that the immune system does not play a major role in controlling this type of tumor, there is reason to believe that the full force of the immune system could be brought to bear on cancer through a vaccination strategy. In general, once lymphocytes have become involved in an immune response, the immune system is armed and ready to respond in a much quicker fashion should the host be exposed again to the same antigen. The immune response thus learns from its early experiences and remembers its past encounters. This fact underlies our ability to vaccinate against certain important infectious diseases. By deliberately exposing individuals to dead or crippled pathogens, or to important antigens from these pathogens, we arm the immune system to be able to deal appropriately with the pathogen if the individual should ever be exposed to it in the future. This approach could be used to prevent breast cancer. Ideally, antigens characteristic of and specific to breast cancers would be used to stimulate an immune response that could then recognize and kill any such cancer should it begin to develop. The challenge here of course is to identify antigens that define the cancer and then to produce them in such a form that they could be introduced into someone to induce a protective immune response. The approach is used in infectious disease research but has to date been successful only in a limited number of instances and it is true to say that despite great investment, many of our most successful vaccines continue to utilize whole dead or crippled pathogens rather than defined antigens. Such a "crude" vaccination approach has also been examined for cancer, in settings where surgically removed tumor cells are reintroduced as vaccine into the patient in a form that is highly immunogenic and more likely to activate the innate defenses or directly activate lymphocytes. Most success using the vaccination approach for cancer has probably come in melanoma, where defined cancer related antigens and whole tumor preparations have been utilized with varying, but sometimes dramatic success.
A major difference between vaccination to prevent infectious disease and vaccination against cancer is that usually the former is used as a preventative whereas the latter presently is considered as part of a treatment regimen in people who already have disease. Although this vaccine therapy approach has been proven to work, there are several complicating factors not least of which is that as is the case in many cancers, breast cancer development is associated with a general immunosuppression that probably further limits the ability of the host's immune system to respond effectively to the tumor and possibly to vaccination. This immunosuppression is the result of the production by tumor cells of molecules that can directly inhibit or otherwise affect lymphocyte function. Unfortunately, radio and chemo-therapy, which target unregulated, fast-dividing cancer cells, also target the immune system, which is itself comprised of highly regulated rapidly dividing cells. Thus cancer itself, plus common treatments for cancer, can have a deleterious effect on the ability of the host to mount an immune response. Nevertheless, on a more positive note, surgical removal of tumors often is associated with a return of immune function and it would be envisaged that this would present the optimal opportunity for therapeutic vaccination.
In addition to vaccination, less specific immunotherapies against cancers have and continue to be used, sometimes with success. Examples include the administration of dead pathogens or pathogen components as immunostimulants which activate the innate defense system creating an environment in which some damage might be done to the tumor and in which tumor specific lymphocyte responses might be more likely to develop. In an attempt to make these treatments less ill-defined, most recent approaches utilize purified versions of the effector molecules generated by the innate defense system in response to exposure to pathogens.
Many Carcinogens are Immunosuppressants: What's the Connection?
Many carcinogens, at least as used experimentally, are immunosuppressive. Thus it seems reasonable to question whether suppression of the immune system is a major factor leading to the development of tumors in response to environmental exposure to carcinogens. The argument against this would again be that immunodeficient individuals seem no more prone than the rest of the population to developing tumors against environmental carcinogens.
Edward J. Pearce, Associate Professor of Parasitology
College of Veterinary Medicine, Cornell University