[A retrospective view of tumor immunology]

The story of tumor immunology includes periods of hope followed by ones of disenchantment as far as clinical applications are concerned. In antiquity, cancer was considered "contrary to Nature", a concept which was confirmed by Ehrlich at the beginning of our century when the layed down the foundations of immunology. The latter was defined as the defence against all "non-self" intruders, including cancer, as opposed to the protection of "self". This concept was further accentuated by the theory immune surveillance proposed by Burnet in 1969 which implicated a destruction of nascent neoplastic cells by T lymphocytes. To increase host defence was the basis of tumor immunotherapy with BCG, levamisol and other adjuvants. The appearance of the nude mouse, athymic, and yet free of spontaneous tumors, led to a new paradigm, the network theory proposed by Jerne. This was based on immunological homeostasis implicating that both "self" and "non-self" can be rejected and tolerated. Cancer gradually ceased to be considered as "contrary to Nature". As for the proposed viral etiology of cancer which was the basis of the National Cancer Act signed by Nixon in 1971, this led to various breakthroughs and Nobel Prizes (Table 1), to discoveries such as reverse transcriptase, cellular oncogenes, tumor suppressor genes, which gave a new explanation for neoplastic transformation. The latter can now be considered as the consequence of a cascade of molecular events which include oncogene expression, anti-oncogene deletion, etc... converting, step by step, for instance, a polyp into a colon cancer and its metastases. The availability of monoclonal antibodies capable of attacking tumor cells did not lead to the expected success because of the complexity of the immune system. Attempts at a better understanding of the latter have led to a subdivision of the T lymphocyte CD4 population into Th1 and Th2. Th1 favor rejection (tumoral, fetal or of transplants) through the elaboration of IL-2, IFN and TNF while Th2 led to tolerance or acceptation through the production of IL-4, IL-5 and IL-10: both functions neutralize each other establishing a "normal" equilibrium Th1 vs Th2. This could explain the state of "tumor dormancy" or tumors in situ which are apparently quite frequent. That any immunological stimulation would cause these dormant tumors to proliferate is the basis of the immunostimulation theory proposed by Prehn and supported by the clinical observations of Stewart. This new concept has led some authors to propose that instead of destroying the tumor cells an attempt be made to maintain them in a state of dormancy in congenial company with normal cells.