Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

http://science.sciencemag.org/content/sci/331/6024/1565.full.pdf

Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion

The concept that the immune system can recognize and destroy nascent transformed cells was originally embodied in the cancer immunosurveillance hypothesis of Burnet and Thomas. This hypothesis was abandoned shortly afterwards because of the absence of strong experimental evidence supporting the concept. New data, however, clearly show the existence of cancer immunosurveillance and also indicate that it may function as a component of a more general process of cancer immunoediting. This process is responsible for both eliminating tumors and sculpting the immunogenic phenotypes of tumors that eventually form in immunocompetent hosts. In this review, we will summarize the historical and experimental basis of cancer immunoediting and discuss its dual roles in promoting host protection against cancer and facilitating tumor escape from immune destruction.

Cancer immunoediting: from immunosurveillance to tumor escape.

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

The three Es of cancer immunoediting.

The immunobiology of cancer immunosurveillance and immunoediting

The immune system can identify and destroy nascent tumor cells in a process termed cancer immunosurveillance, which functions as an important defense against cancer. Recently, data obtained from numerous investigations in mouse models of cancer and in humans with cancer offer compelling evidence that particular innate and adaptive immune cell types, effector molecules, and pathways can sometimes collectively function as extrinsic tumor-suppressor mechanisms. However, the immune system can also promote tumor progression. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. In this review, we discuss the current experimental and human clinical data supporting a cancer immunoediting process that provide the fundamental basis for further study of immunity to cancer and for the rational design of immunotherapies against cancer.

Natural Innate and Adaptive Immunity to Cancer

/pdf/cancer-a-biological-approach-i-the-processes-of-control-ii-57uikisbul.pdf

Cancer—A Biological Approach: I. The Processes Of Control. II. The Significance of Somatic Mutation

There is still an active body of opinion that would regard cancer as a parasitic disease due to infection of cells by extrinsic viruses. Such an attitude has the great attraction that it suggests straightforward approaches to the prevention of cancer by immunological methods and holds out more hope of an eventual effective chemotherapy. As various writers have pointed out, the claim that some neoplastic processes are due to virus infection is not inconsistent with a recognition of the overriding importance of somatic mutation. Any claim that all cancers are of infective character is unjustified and frankly absurd in the present state of knowledge. It has never been easy to define a virus, and the recognition of provirus in bacteria, with the convincing evidence that it is intimately built into the host's genetic mechanism, has now made it even more difficult. Any definition must cover the fact that there are two very different systems from each of which by appropriate manipulations a continuing sequence of typical virus infections may be produced. These are respectively the infective particle and the infected host cell. A virus, in the conventionally understood form of a population of infective virus particles, can be defined as a self-replicating agent or organism smaller than bacteria and capable of multiplication only within living susceptible host cells. It may be desirable to add certain qualifications when we have to discuss demonstrable or hypothetical self-replicating subcellular entities. A virus particle must be shown to carry specific patterns in protein and nucleic acid which are different from those of the host cell and which are not derived genetically from the host species or any species related to it. At a certain stage of infection, host cells may contain no virus demonstrable by the classic method of breaking up the cell and inoculating the product into other susceptible cells. There is other evidence that at this stage the cells do not contain formed virus particles. Under certain circumstances this phase may be prolonged. Its existence can be recognized either by providing a situation where infective virus particles will develop and be identified by standard methods or by demonstrating specific virus antigen in or liberated from the cells. In general a virus (in the sense covering both the infective and vegetative phases) can be recognized only if it produces cytopathogenic effects in some type of host. It is by no means necessary, however, that intracellular

/pdf/cancer-a-biological-approach-iii-viruses-associated-with-3zby99m0iq.pdf

Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications.

At the beginning of 1961, I think it is fair to state, the function of the thymus was unknown. To-day I believe that we have the basis for an understanding of its function on which experimental and clinical study will gradually build up a substantial structure of theoretical and practical knowledge. The thymus, at least in the child, is a large organ, and it is rather satisfying to feel that we are taking part in the elucidation of the function of the last major organ of the body to remain a mystery. The thesis I wish to support is that in mammals the thymus is an organ in which primary proliferation and differentiation takes place of the lymphocytic cell lines which will subsequently be responsible for a large portion of the immunological activity of the body. In the chicken this function appears to be shared by another important lymphoid organ, the bursa of Fabricius, and there is a good deal to suggest that in mammals we have yet to determine where the activities that correspond to those of the avian bursa should be located.

https://www.bmj.com/content/bmj/2/5308/807.full.pdf

Role of the Thymus and Related Organs in Immunity

Medicine has been the mother of all the biological sciences. There are many reasons for this, but one of them is specially relevant to my present topic. It is simply that while the body functions smoothly things are taken for granted. It is only when things go wrong that it becomes possible to perceive that there is something in normal function which requires understanding. The central theme of these lectures is that the phenomena seen clinically in diseases of the so-called auto-immune group can be interpreted to throw light on the nature of immunological processes, and equally that recent developments in theoretical immunology are becoming highly relevant to clinical medicine. We were all taught to regard antibody production and other immune responses as manifestations of a process of defence against invading micro-organisms or any other type of foreign material entering the tissues. In some way the body was enabled to recognize what was foreign and to swing into action the immunological responses needed to speed its removal. The meaning of foreignness was something that seemed to worry nobody. Only with the recognition that there are disease conditions in which antibody is actually directed against body components-acquired haemolytic anaemia, for instance-did a real sense of the importance of the body's ability to differentiate between self and not self come into being. In Melbourne I am closely associated with our Clinical Research Unit, but only as an immunological consultant without clinical responsibility. My approach to the medical problems must necessarily be at the theoretical level, but at the present time I believe that it is better to try to present a working approach to generalization about the auto-immune diseases than to add to the volume of clinical descriptions and therapeutic trials. The approach will be based very largely on a concept of immunity which is still a heterodox one-although it has some distinguished proponentswhich has been called the clonal selection theory (Burnet, 1959). The stimulus to adopt such a theory came largely from a consideration of the pathology of immunity, and perhaps its chief virtue over earlier theories is its direct relevance to the problems of autoimmune disease. The Facts of Immunity Every human being has an immunological individuality that differentiates him from every other person-with only the minor qualification that identical

/pdf/auto-immune-disease-i-modern-immunological-concepts-az0b3dkr3z.pdf

Auto-immune Disease: I. Modern Immunological Concepts

genetics, which could have advanced rapidly with the rediscovery of Mendel's work, failed to achieve this advance until many years later, and there is some irony in the fact that during these wasted years it was the work of the anti-Mendelians that was outstanding. The clarification of the status of familial disease made available a mass of clinical observations that in turn could elucidate Mendelian principles. Over the years came recognition of the specific problems of Mendelian ratios in the relatively small numbers presented by human families. There also came the concepts of expression and of penetrance, particularly in dominant disorders, and the concepts of incomplete recessiveness and the carrier state. The multiplicity of blood groups brought much elucidation on multiple allelomorphs. The interaction between heredity and environment seen in an extreme form in the fractures induced by minimal trauma in fragilitas ossium could also be seen in more subtle aspects in other disorders, including possibly tuberculosis and other infectious diseases which were operative only in a susceptible genetic constitution. Haemolytic jaundice of infants was seen not to be strictly genetic in character but a form of induced autolysis because of genetic incompatibility. To-day both the significance and the scope of medical genetics are increasing rapidly. As the infectious diseases are being brought under control, the constitutional factors of disease are once again assuming a dominant place in pathology, and it is becoming increasingly obvious that these are largely determined genetically. Moreover, an extensive range of clinical appearances previously considered environmental in origin have come to be recognized as merely different stages of hereditary diseases which run an evolutionary course in post-natal life and thus present different aspects in different members of a family. But present-day medical genetics is no longer a matter of collecting and interpreting pedigrees. Statistical methods have made possible the assessment of the frequency of pathogenic genes and of mutation rates in the population, so that genetically determined disease is no longer an altogether unknown quantity. Recognition of the inborn errors of metabolism of Garrod have led to intensive studies of enzyme systems at the cellular level, and there is hope that the uncovering of biochemical faults as the mechanism of genetic disorders may open therapeutic possibilities. Some such possibilities are already being effected, as, for instance, the relative control of galactosaemia by excluding galactose in the infant's food. Faulty protein synthesis is yet another possible basis of genetic disorders. This is seen most strikingly in the current studies on sickle-cell anaemia and the other haemoglobinopathies, and it is likely that many other hereditary anomalies, including such classical affections as retinitis pigmentosa, may come to be explained in this manner. Ever since the gene came to be located in the chromosome, the possibility of chromosomal anomalies as a cause of hereditary disease has been under consideration. Until recently such anomalies-observed microscopically-were held to be incompatible with life if they were present in any but a minimal form. It is now clear that chromosomal anomalies are in fact a substantial cause of pathological states. Down's syndrome (mongolism) is an outstanding example. The gene itself has followed the atom in ceasing to be the irreducible particle of matter. There is evidence that the genewhich may have a thickness of a millionth of a millimetre-is itself a complex of thinner segments each with its specific effect. The intensive chemical studies on deoxyribose-nucleic acid (D.N.A.) have bearings on both chromosomes and genes.

https://www.bmj.com/content/bmj/1/5431/338.full.pdf

Somatic mutation and chronic disease.

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