By David N. Leff
A faith-based doctrine called ¿immune surveillance¿ held sway among immunologists and oncologists for decades during the late 20th century. It preached that the immune system recognizes and destroys tumor cells, which are constantly arising during the life of the individual. An elaborate in vivo experiment in the 1980s proved this highly controversial dogma to be neat, plausible ¿ and wrong.
¿The concept actually was proposed in the 1950s, ¿60s and early ¿70s,¿ recalled immunologist and molecular microbiologist Robert Shreiber. ¿Its protagonists made the hypothesis based on what they knew of how the immune system works. Like all good scientific theories, it was set up for experimental challenge by a research group at the Memorial Sloan-Kettering Cancer Center in New York. They did very extensive and carefully performed experiments to substantiate or invalidate immune surveillance, using a nude mouse. This animal was thought to be totally lacking in lymphocytes ¿ T and B cells ¿ hence, was 100-percent immunodeficient.
¿Their experiments¿ Shreiber continued, ¿showed that immune-defenseless nude mice did not develop tumors more rapidly or in greater numbers than wild-type animals, either when challenged with sure-fire carcinogens, or when allowed to age ¿ a risk factor for spontaneous tumor formation. But, in the 1970s it was not appreciated that the nude mouse still had some basal T-cell function, so was not completely immunodeficient. But the experiments were so well done and so convincing that they are always pointed to nowadays as the classic study that led to the abandonment of the immune surveillance doctrine.¿
Shreiber, who holds an endowed chair of pathology and immunology at Washington University, St. Louis, is senior author of a paper in the current issue of Nature, dated April 26, 2001. Its title: ¿IFNg and lymphocytes prevent primary tumor development and shape tumor immunogenicity.¿
¿The article presents three basic findings,¿ Shreiber told BioWorld Today. ¿First, this study probably represents the best demonstration to date that the immune system can in fact protect individuals from the development of cancer. This sets the stage to look forward in terms of what happens when tumors do form in the presence of the immune response.¿
Double Dealing By Immune Defenses
¿That brings us,¿ Schreiber continued, ¿to the second finding, that tumors developed in immunocompetent individuals actually have been altered. They¿ve been shaped by the process of the immune attack against them, and actually become tumors that have found a way of escaping detection by the immune system. Therefore, paradoxically, as the result of the immune action on them during their development, they¿re actually more aggressive tumors than before. I think that therapeutically this is important to realize, because the field is hoping to use immunotherapy to treat tumors.
¿Which leads on to the third finding,¿ he said, ¿that if, in fact, we happen to use one type of manipulation that had one of these tumors, which had been edited by the immune system, we¿d be able to induce a very powerful immune response against even the edited tumors.¿
Shreiber explained: ¿We felt that a name change was critical here, because the concept of immunosurveillance not only evokes a great deal of scientific history but also a great deal of scientific emotion. Moreover, the concept of surveillance suggests that the immune system is acting right at the very beginning of the malignant transformation process ¿ as if that first cell goes through something on its way to becoming a tumor cell. We believe that¿s not a sufficient signal to even alert the immune system. That¿s the good news.
¿But it also gives us the contrary ability to say the immune system can lead to the production of more aggressive tumors through the selective pressure that it puts on a developing tumor in an immunocompetent host. That¿s the bad news.¿
Two critical in vivo experiments bear out the Nature paper¿s conclusions:
¿In one,¿ Shreiber recounted, ¿we took genetically identical mice, which only had one engineered gene defect ¿ absence of the RAG2 gene ¿ and therefore lacked protective lymphocytes. The other cohort ¿ wild-type mice ¿ had a normal RAG2 gene.
¿We injected a chemical carcinogen, methylcholanthrene [MCA] into their skin,¿ he related. And over 160 days some mice developed tumors right at the site of injection. We were able to show that administration of MCA into the RAG2-deficient mice led to the formation of tumors more rapidly, and in greater numbers, compared to wild-type, RAG2-positive, animals. Overall, we used maybe 200 to 300 mice in this experiment. It parallels the fact that many human cancers are caused by carcinogens to which the skin is exposed ¿ as are the lungs.
¿On the bad news side,¿ Shreiber related, ¿when MCA-induced tumors from normal mice were transplanted into healthy normal animals, they continued growing. But eight of 20 tumors from RAG2-lacking mice transplanted into healthy animals were rejected. Apparently, the immune system in these healthy mice was better equipped to recognize ¿ and reject ¿ tumor cells from RAG2-deficient animals than tumor cells that had developed in mice with intact lymphocytes.¿
Geriatric Mice Grew Spontaneous Tumors
¿In a corollary to these experiments,¿ he said, ¿we asked whether animals as they age develop tumors spontaneously. This was an experiment that required a great deal of patience. It meant setting aside large numbers of mice in carefully controlled environment conditions in the animal room, and simply letting them grow old. Then we watched these animals as one would watch a normal, aging human individual by giving checkups, and looking for the development of tumors. This set of experiments took about four years to complete.
¿In these cases,¿ Shreiber said, ¿we found that the animals that were immunodeficient developed a number of different kinds of spontaneous tumors. Perhaps of potentially most interest is the appearance of breast tumors in half of the group that were both immunodeficient and lacked responsiveness to gamma interferon. These tumors were never seen in the wild-type animal.
¿We¿re hoping,¿ he concluded, ¿that one of the benefits of our work will be at the very basic level, as a definition of novel proteins that are important in cellular transformation. This, of course, could provide a whole new range of therapeutic targets that have never been seen before.¿