For many years immunologists have been well served by the viewpoint that the immune system's primary goal is to discriminate between self and non-self. I believe that it is time to change viewpoints and, in this essay, I discuss the possibility that the immune system does not care about self and non-self, that its primary driving force is the need to detect and protect against danger, and that it does not do the job alone, but receives positive and negative communications from an extended network of other bodily tissues.

/pdf/tolerance-danger-and-the-extended-family-1qfdhdej1x.pdf

Tolerance, danger, and the extended family.

Given the vast number of genetic and epigenetic changes associated with carcinogenesis, it is clear that tumors express many neoantigens. A central question in cancer immunology is whether recognition of tumor antigens by the immune system leads to activation (i.e., surveillance) or tolerance. Paradoxically, while strong evidence exists that specific immune surveillance systems operate at early stages of tumorigenesis, established tumors primarily induce immune tolerance. A unifying hypothesis posits that the fundamental processes of cancer progression, namely tissue invasion and metastasis, are inherently proinflammatory and thus activating for innate and adaptive antitumor immunity. To elude immune surveillance, tumors must develop mechanisms that block the elaboration and sensing of proinflammatory danger signals, thereby shifting the balance from activation to tolerance induction. Elucidation of these mechanisms provides new strategies for cancer immunotherapy.

Does the Immune System See Tumors as Foreign or Self

The Journey from Discoveries in Fundamental Immunology to Cancer Immunotherapy

Relatively large numbers of nonimmune spleen cells do not protect against the local growth of two lymphomas. However, this heterogeneous population of splenic lymphocytes contains a subset of cells that efficiently protects against in vivo tumor growth. This cell population (cell-surface phenotype Thyl.2(-)Ig(-)Ly5.1(+)) represents less than 5 percent of the spleen cell population and is responsible for in vitro NK-mediated lysis. Although these studies clearly and directly demonstrate that Ly5(+) NK cells selected from a heterogeneous lymphoid population from nonimmune mice can protect syngeneic mice against local in vivo growth of two different types of tumor cells (in contrast to other lymphocyte sets within the spleen), they do not directly bear upon the role of NK cells in immunosurveillance. They do indicate that highly enriched Ig(-)Thyl(-)Ly5(+) cells, which account for virtually all in vitro NK activity, can retard tumor growth in vivo. It is difficult to ascribe all anti-tumor surveillance activity to NK cells, because they probably do not recirculate freely throughout the various organ systems of the body. Perhaps NK ceils may play a role in prevention of neoplastic growth within discrete anatomic compartments where there is rapid differentiation of stem cells to mature progeny (e.g., bone marrow, spleen, and portions of the gastrointestinal tract)and may normally act to regulate the growth and differentiation of non-neoplastic stem cells. Long-term observation of chimeric mice repopulated with bone marrow from congenic or mutant donors expressing very low or very high NK activity may help to answer these questions.

/pdf/direct-evidence-that-natural-killer-cells-in-nonimmune-57hg8lu7vy.pdf

Direct evidence that natural killer cells in nonimmune spleen cell populations prevent tumor growth in vivo.

Most oncologists are probably of the opinion that the immune system constitutes an important defense against the occurrence of cancer, a concept embodied in the term \"immunologic surveillance\" (1). However, increasing numbers of cognoscenti are now persuaded that the role of immunity has, in most tumor systems, been vastly overrated (2-5). I have begun to entertain the diametrically opposite hypothesis that an immune reaction, rather than killing incipient neoplasms, may actually stimulate them to grow (5-7). My purpose in this editorial is not to persuade you that the immune re action is a significant cause of tumor growth, but rather to persuade you that this hypothesis merits serious consideration. Before one questions whether the action of an immune response is predominantly stimulatory or inhibitory to target tumors, it would be weIl to ask whether or not the neoplasm stimulates an immune response of any kind. The answer may be affirmative in some systems, but it is by no means c1ear that this is always so, or indeed that this is frequently so. There appears to be no question about the fact that most tumors induced in the laboratory, either by viral, chemical, or physical agents are, at least potentially, immunogenic (8). The growths of transplants of these tumors can often be modified by specific immunization; in vitro tests of various kinds are often positive, and immunodepression of the host animals often leads to faster growth of transplants. Furthermore, in some viral systems it is c1ear that immunodepression potentiates the appearance and growth of the primary, untransplanted neoplasm, and converse1y, that vaccination is successful (8). In chemical tumor induction, potentiation of oncogenesis by immunodepression is difficult to demonstrate, perhaps partly because of the immunodepression produced by the oncogen itse1f (9). Positive, statistically significant reports exist, but they are nonetheless usually of marginal degree (10, 11). Failures have also been revealed, and one suspects that many negative results have not been reported (2). Under these circumstances, the real significance of the positive reports remains questionable. Most important is the fact that so-called spontaneous tumors in rodents, i.e., tumors that arise in low frequency, often in older animals and for no overt cause, are se1dom immunogenic (12, 13). (By immunogenic, I refer only to the capacity of a tumor to induce an immunity in vivo that will restriet to some degree the subsequent growth of implants.) In chemically induced tumors, immunogenicity tends to be directly re1ated to the concentration of the inducing oncogen; low concentrations that presumably mimic the spontaneous condition produce tumors of little or no immunogenicity (14). The reason for the low or nonexistent immunogenicity of spontaneous tumors or those induced by low doses of carcinogen is not yet known, and indeed it may vary from case to case. An absolute paucity of tumorassociated antigens is to be suspected, but alternatives such as induction of \"blocking\" factors, shedding of antigen, e1icitation of suppressor cells, or induction of a competing tumor-stimulatory reaction have, in most instances, not been ruled out. The possibility of course exists that \"spontaneous\" turnors might be more immunogenic at their inception and that this property is lost via immunoselection during tumor \"progression\" (8). That some selective effects do occur in relation to tumor immunogenicity has been directly demonstrated by Bartlett (15) and Bubenik et al. (16). However, tumors that arise in the immunologically free confines of tissue culture or in diffusion chambers are, unless a chemical or virus has been deliberately added, seldom immunogenic. This suggests that immunose1ection is not the fundamental reason for the lack of immunogenicity in spontaneous tumors (15, 17-20). Immunogenicity seems to be a property initially conferred by the oncogen, if one is overtly present; immunoselection can certainly then occur but need not be invoked to account for the lack of immunogenicity of spontaneous tumors or tumors induced by low doses of carcinogens. That the immune system does interact with spontaneous human tumors has been forcibly argued by loachim (21) in defense of the concept of immunologic surveillance. He has rightly pointed out that many human tumors, especially in the early stages of their evolution, are associated with an intense infiltration of lymphocytes and/or related cells. It seems reasonable to suppose that this infiltrate is indicative of immunologic recognition of the neoplasm. Furthermore, the presence of this infiltrate suggests that many human tumors may result from the action of chemical carcinogens and others from the action of oncogenic viruses. How many human neoplasms are really spontaneous in the sense of the spontaneous rodent tumors? In the rodent, the term spontaneous is perhaps best equated with tumors that arise infrequently and sporadically. However, this infrequency is usually in an inbred population in which all the members are at equal genetic risk. In man, where genetically susceptible individuals cannot yet be identified, it is possible that some tumors, thought of as spontaneous, may actually occur in nearly 100 % of the genetically susceptible populationl Are these then to be considered spontaneous, or are they more akin to those rodent tumors induced in high frequency

Immunostimulation of the lymphodependent phase of neoplastic growth.

Are malignant clones, generated by somatic mutation, the selective pressure that has maintained cell-mediated immunity, as expressed in graft rejection, during the process of evolution? It may seem awkward to open a contribution to 'Experiments and the concept of immune surveillance' with such a Darwinian question since evolution is a long-term experiment and the period of our observation is confined to a small segment of it. However, the answer to this question is crucial for the acceptance or rejection of the hypothesis of Immunological Surveillance. Three sets of observations made in the athymic nude mouse are directly related to this issue: First, is the ready and permanent acceptance of foreign tissue grafts in nude mice. Second, the near total absence of spontaneous malignant tumours in nude mice. Third, the life span of the nude mouse is inversely proportional to the amount of environmental stress contributed by the microbiological milieu that the animal is exposed to. In view of this evidence we argue that the microbiological milieu and not spontaneous tumour generation is the selective pressure that has maintained cell-mediated immunity during evolution. In the following, we char-

The Nude Mouse vs. The Hypothesis of Immunological Surveillance

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Josrgen Rygaard

Author Tools

Chat about Author

Papers

The Nude Mouse vs. The Hypothesis of Immunological Surveillance