The concept of immunological surveillance.

The effect of immunosuppressive therapy on the incidence of malignancy was examined in BALB/c mice. In a short (31-week) protocol study, malignancy was induced by inoculating animals with 10(2.1) ID50 of lymphatic leukemia virus. Antilymphocyte antiserum and azathioprine increased the mortality and shortened the latency period of leukemia. Combining these two agents had a synergistic effect. The concept of immunological surveillance was investigated in a long-term protocol using the identical animal and immunosuppressive systems. Mice did not receive leukemia virus and were observed for development of spontaneous malignancy. Significant immunodepression was demonstrated after 348 days of immunosuppressive therapy. After two years, all surviving animals were killed and examined for neoplasia. There was no evidence that immunodepression increased the incidence of spontaneous malignancy. Immunosuppression adversely influenced exogenously administered, virus-induced murine leukemia. However, immunosuppressive therapy was not innately oncogenic and the concept of immunological surveillance was not confirmed.

Three peculiar features have developed in recent years regarding the concept of immunological surveillance (IS). Firstly, the interest in the subject by bona fide immunologists who in the past only had marginal attachment to tumor immunology [1–7], in one case producing actual experimental work [2, 3] and in another [7] by involvement in natural killer (NK) cell research. Secondly, the possible ‘rescue’ of IS [8] as a viable hypothesis by the recent explosion of information on natural-cell-mediated cytotoxicity (N-CMC), especially on NK cells and similar effector mechanisms in animals and humans [9]. The third, and most important point concerning the actual role of the IS hypothesis in the analysis of clinical data, will be discussed at the end of this Introduction. Implied in the first point are also the views that NK cells may be possible mediators of IS [3, 6, 7], with very little else that can be considered as new insights into the problem. Especially since the possible role of NK cells in IS was proposed some time ago by several tumor immunologists [10–14] as well as by researchers in the NK area [12–14]. What was aptly termed as the ‘rescue’ of IS by NK cells [8] can still be considered simply as an adjustment of this persistent theory to the total debacle of the concept of IS as a general phenomenon that applies to all forms of malignancy and to the notion of being mediated by T cells, as originally proposed by Burnet [15].

Immunological surveillance against cancer: Critique of an established hypothesis

CHAPTER VIII - IMMUNOLOGICAL SURVEILLANCE

Immunological Surveillance: Pro and Con

The concept of immunological surveillance, a monitoring process in which the immune system detects and destroys by several effector mechanisms, virally infected and neoplastic transformed cells in the body, was developed more than 50 years ago. Based on current research, it is clear that the immune system can recognize and eliminate transformed cells. An increasing number of studies has investigated the immune system in cancer patients and how it is prone to immunosuppression, due in part to the decrease of lymphocyte proliferation and cytotoxic activity. Such weakened immune system is then unable to fully accomplish its role in immunological surveillance, allowing nascent transformed cells to escape the selective pressure of the immune system. The main goal of cancer immunotherapy has been to reawaken the immune system from a suppressive slumber to enable it to attack cancer cells once again. As the results from the last 10 years attest, cancer immunotherapy is the best strategy to restore the activity of the immune system and unleash its potential to destroy cancer cells in cancer patients. This chapter aims to discuss the recent findings on immune monitoring studies and the use of immune checkpoint inhibition in cancer immunotherapy.

CHAPTER I - INTRODUCTORY CONSPECTUS

Antigens which distinguish neoplastic cells from their normal counterparts can be identified in some, but by no means all, experimental tumours. Specifically immunized hosts can in appropriate circumstances reject small tumours immunologically. The mechanisms of rejection remain unknown. The extent to which most human neoplasms excite a rejection reaction is still not clear. While the behaviour of neoplasms appears to be influenced by the immune system, the concept of immunological surveillance against neoplasia is losing support. Clinical immunotherapy has not yet achieved notable success, and remains empirical.

The Concept of Immunological Surveillance against Neoplasia

The capacity of the immune system to control cancer

Since the time of Paul Ehrlich 100 years ago, we have known that the immunological apparatus somehow inhibits most damaging autoimmune responses while permitting a response to exogenous immunogens. With the discovery of tolerance, the concept of immunological surveillance, and especially with the discovery of HLA restriction of T-cell recognition, the term "the immunological self" and the phrase "self-nonself discrimination" have gained wide currency. Immunology has been called "The Science of Self", and self-nonself discrimination has been assigned as the driving force for its complex evolution. The concept of self has thus been given such mystical trappings since the time of Macfarlane Burnet that recent workers have felt free to pronounce it the central paradigm of modern immunology, and to claim to overthrow it! In this article, we challenge some of the more egregious claims about the immunological self by recalling important historical findings, by reviewing the mechanisms of Darwinian evolution, and by remembering that the general pathology of immunogenic inflammation shows that the immune response cannot discriminate between the benign and the noxious.

The discovery of tumor-specific antigens and tumor-specific immune responses in both animals and humans with malignant disease has increased understanding of the host defense mechanisms in the etiology and pathogenesis of cancer. However, before these tumor-specific immunological phenomena were clearly documented in man, it was strongly suspected that host defense mechanisms or their failure played a role in the etiology and pathogenesis of tumors. As these tumor-specific immune mechanisms were discovered in man, the concept of immunological surveillance was developed.(1)

The concept of immunological surveillance as a major host defense against foreign cells has been used to explain both graft rejection and the recognition and elimination of cancer cells (Thomas, 1959; Burnett, 1970). Simply stated, this theory proposes that lymphocytes possess the ability to recognize and destroy cells of a foreign graft or cancer cells that are recognized as nonself by the host. The rapid development of this area of investigation into cancer immunology was so heavily weighted in the direction of cell-mediated immune reactions as to neglect the role of humoral immune parameters in the host response. Recent experiments have demonstrated that complement can play a limiting role in both graft rejection (Koene et al., 1973) and tumor cell destruction (Old et al., 1967; Kassel et al., 1973). These results emphasize the need to reevaluate our present concepts of tumor immunology. This was done in a recent review by Nishioka (1976), who reiterates the need to take an overview of the entire immune system and the interplay of its component parts in the tumor-host relationship. Nishioka divides the immunological surveillance system into four segments: (1) the classical pathway of the complement system; (2) the C3 shunt or alternate pathway of complement; (3) the cell-mediated immunity (mainly lymphocytes) system; and (4) the immunoglobulin-mediated system. The stress placed on the role of the lymphocyte-mediated system in tumor immunology thus covers only one-fourth of the host defense mechanism, whereas the complement system works synergistically with those segments of the immune system involving immunoglobulins, lymphocytes, macrophages, granulocytes, erythrocytes, and platelets.

The concept of immunological surveillance against neoplasia was initially proposed by Ehrlich in 19091, later rephrased by Thomas2 and substantially developed by Burnett The concept states that the normal function of the immune system, or more precisely the cell-mediated immunity carried out by thymus-derived (T) lymphocytes, is to recognize and destroy newly appearing tumour cells in situ. The concept was developed at a time when the only known function of T lymphocytes was to destroy foreign grafts. It gave a satisfying explanation of an otherwise puzzling phenomenon and it was rapidly accepted by most workers in the field and by virtually all those outside the field.

The concept of immunological surveillance implies that immunogenic variants of tumor cells arising in the organism can be recognized by the immune system. Tumor progression is provided by somatic evolution of tumor cells under the pressure of the immune system. The loss of MHC Class I molecules on the surface of tumor cells is one of the most known outcomes of immune selection. This study developed a model of immune selection based on the immune response of TCR 1d1 single β-chain transgenic B10.D2(R101) (KdIdDb) mice to allogeneic EL4 (H-2b) thymoma cells. In wild-type B10.D2(R101) mice, immunization with EL4 cells induced a vigorous CTL response targeted to the H-2Kb molecule and results in full rejection of the tumor cells. In contrast, transgenic mice developed a compromised proliferative response in mixed-lymphocyte response assays and were unable to reject transplanted allogeneic EL4 cells. During the immune response to EL4 cells, CD8+ T-lymphocytes with endogenous β-chains accumulated predominantly in the spleen of transgenic mice and only a small part of the T-lymphocytes expressing transgenic β-chains became CD8+CD44+CD62L− effectors. Then, instead of a full elimination of tumor cells as in wild-type mice, a reproducible prolonged equilibrium phase and subsequent escape was observed in transgenic mice that resulted in death of 90% of the mice in 40–60 days after grafting. Prolonged exposure of tumor cells to the pressure of the immune system in transgenic mice in vivo resulted in a stable loss of H-2Kb molecules on the EL4 cell surface. Genetic manipulation of the T-lymphocyte repertoire was sufficient to reproduce the classic pattern of interactions between tumor cells and the immune system, usually observed in reliable syngeneic models of anti-tumor immunity. This newly-developed model could be used in further studies of immunoregulatory circuits common for transplantational and anti-tumor immune responses.