Theory Of Immune Surveillance Research Articles

Atopic diseases and oncopathology. What do they have in common? A review

The increasing prevalence of cancer worldwide has influenced the interest of researchers to search for factors that may trigger oncogenesis in order to prevent and treat cancer. There is a burning question, can allergic diseases cause or prevent cancer? Numerous epidemiological studies have been conducted that have evaluated aspects of the relationship between allergic diseases and the occurrence of cancers of various localizations. The results of most of these studies are inconsistent, both in the nature of the course of the disease and in the variety of localizations of the occurrence of cancer. In this connection, two basic theories were suggested: the theory of immune surveillance and the theory of inflammation. This review analyzed current scientific work to estimate the incidence of neoplasms against the background of atopic diseases. The analysis of clinical studies shows inconsistent results of the association between allergic diseases and cancer. Several studies an inverse relationship between atopic diseases and cancer risk, which supports the theory of immune surveillance [brain tumor (glioma), pancreatic cancer, colorectal cancer, non-Hodgkin's lymphoma, and breast cancer, cancer of the mouth and throat, larynx]. At the same time, a number of studies note a positive association between atopic diseases and cancer, which confirms the theory of chronic inflammation (lung cancer and colorectal cancer combined with bronchial asthma). The lack of an unequivocal explanation testifies to the urgency of long-term prospective studies aimed at studying the risk factors of cancer in combination with atopic diseases with the subsequent development of risk scale for the purpose of patient stratification, screening, development of early detection programs and new approaches to the treatment of malignant neoplasms.

The Pattern of Malignancies in Down Syndrome and Its Potential Context With the Immune System.

The immune surveillance theory of cancer posits that the body's immune system detects and destroys randomly occurring malignant cells. This theory is based on the observation of the increased frequency of malignancies in primary and secondary immunodeficiencies, and is supported by the successful demonstration of immune augmentation in current oncological immune therapy approaches. We review this model in the context of Down syndrome (DS), a condition with a unique tumor profile and various immune defects. Children and adults with DS are more prone to infections due to anatomical reasons and a varying degree of T- and B-cell maturation defects, NK cell dysfunction, and chemotactic or phagocytic abnormalities. However, despite an increased incidence of lymphoblastic and myeloblastic leukemia of infants and children with DS, individuals with DS have a globally decreased incidence of solid tumors as compared to age-adjusted non-DS controls. Additionally, cancers that have been considered “proof of immune therapy principles,” such as renal carcinoma, small cell lung carcinoma, and malignant melanoma, are less frequent in adults with DS compared to the general population. Thus, despite the combination of an increased risk of leukemia with detectable immune biological abnormalities and a clinical immunodeficiency, people with DS appear to be protected against many cancers. This observation does not support the immune surveillance theory in the context of DS and indicates a potential tumor-suppressive role for trisomy 21 in non-hematological malignancies.

Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies.

Elimination of cancer cells through antitumor immunity has been a long-sought after goal since Sir F. Macfarlane Burnet postulated the theory of immune surveillance against tumors in the 1950s. Finally, the use of immunotherapeutics against established cancer is becoming a reality in the past 5years. Most notable are the monoclonal antibodies (mAbs) directed against inhibitory T-cell receptors cytotoxic T lymphocyte antigen-4 and programmed death-1. The next generation of mAbs targeting T cells is designed to stimulate costimulatory receptors on T cells. Here we review the recent progress on these immunostimulatory agonist antibodies against the costimulatory receptors CD137, GITR, OX40, and CD27.

Advances in cancer immunology and cancer immunotherapeutics

<p>The immune system plays an important role in protection against tumor growth. The theory of immune surveillance has evolved today leading to recent advancement in field of cancer immunotherapy. Here, we have revisited the basic structure of immune system with emphasis on its interaction with tumor cells. Also discussed briefly, is the landscape of current cancer immunotherapy and the future it holds.</p>

Abstract 660: Pre-symptomatic detection and early treatment of mammary cancer with anti-PD-L1 in a mouse mode

Abstract Cancer kills ~8M people/year and the WHO predicts an epidemic of cancer in the developing world over the next 20 years due to increased longevity. Development of a simple method to detect and treat cancer early could be a solution to this challenge. Here we test this approach in principle in a transgenic mouse mammary tumor model by immunosignature (IMS) diagnostics. IMSs are profiles of antibodies in the blood displayed on a high density peptide array. As previous published data showed, the IMS can distinguish different diseases based on the disease specific antibody profile in the patient, including different cancers and infectious diseases. According to the immune surveillance theory, the immune system, including the humoral immune response, starts to interact with cancer cells as soon as they are transformed. First, we tested if the IMS is sensitive enough to detect the antibody profile change caused by the early tumor development in the FVB-NeuN (MMTVneu/202Mul/J) mammary cancer model. In the FVB-NeuN model, the MMTV promoter activates the wild type rat ERBB2 gene in mammary cells, and every mammary cell potentially can convert into a cancer cell. The transition from normal mammary glands to hyperplasia of FVB-NeuN in mouse starts at 8.6 to 15 weeks after birth. The mice develop the first palpable tumor in one of the ten mammary glands by 19-45 weeks of age with an average age of 32±1.2 weeks in our hands. We collected serum every 4 weeks from the FVB-NeuN mice and the wild type FVB mice for the IMS analysis. The IMS can distinguish the FVB-NeuN mouse from the age matched wild type FVB mouse as early as 12 weeks (Stage-1) before the onset of the first palpable tumor. We also analyzed the IMSs from the Stage-2 (8 weeks before the palpable tumor and so on) to Stage 4. Different IMS of each stage has only partial overlap with the other stages. The cross-stage prediction analysis showed the accuracy of the cancer detection by using different IMS is from 75% to 93%. Second, we determined if early treatment at the time of diagnosis with the checkpoint blockade, anti-PD-L1, would inhibit the tumor growth. A course of 3 injections at the time of diagnosis significantly retarded tumor growth relative to untreated controls. The early treatment elicited long-term protection which could restrict the tumor growth even four months after the treatment. The treated mice presented a specific IMS at 28 days post treatment and 35 days post the first palpable tumor, compared to the untreated mice. This indicates that the early treatment elicited an anti-tumor immune response that could inhibit tumor growth. This preliminary experiment suggests that early diagnosis combined with systemic treatment might be a method to control or eliminate cancer. Citation Format: Hu Duan, Stephen Albert Johnston, Shen Luhui. Pre-symptomatic detection and early treatment of mammary cancer with anti-PD-L1 in a mouse mode [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 660. doi:10.1158/1538-7445.AM2017-660

Modeling of T-lymphocyte extravasation into a lymph node: The connection between the morphological basis of the process and the clonal selection theory

A model of the process of T-lymphocyte extravasation into a lymph node via the high endothelial venules in the course of the immune response has been developed. The histological structure and the morphometric parameters of the lymph node and its venules, as well as the presence of adhesion molecules on the endothelial cells and the speed of T-lymphocyte movement, were taken into account in the model and compared to the basic postulates of the clonal selection theory of immune surveillance. The inability of the venules of the lymph node to provide the passage of a sufficient number of T lymphocytes has been demonstrated; thus, the concept of immune surveillance formulated within the existing immunological theory has been proven inadequate. This finding points to the need for revision of the widely accepted concepts of the emergence of T-lymphocyte specificity and the very foundations of the clonal selection theory.

The concept of immune surveillance against tumors. The first theories.

The immune system plays a major role in the surveillance against tumors. To avoid attack from the immune system, tumor cells develop different strategies to escape immune surveillance. Evidence of immune surveillance comes from both animal models and clinical observations. Mice with a wide variety of immunodeficiencies have a high rate of tumor incidence and are more susceptible to transplanted or chemical carcinogen-induced tumors. Immunosuppressed patients have a high incidence of tumors. However, many patients develop cancer even in the presence of an apparently normal immune system. This indicates that tumor cells are able to escape immune surveillance. The aim of this review article is to summarize the literature concerning the development of the theory of immune surveillance against tumors; to discuss the evidence for and against this theory, and to discuss the concept of immunoediting. Finally, the current approaches in anti-tumor immunotherapy will be analyzed.

Tapping our immune potential to realise the ultimate goal

Tapping our immune potential to realise the ultimate goal

A New Ally against Cancer

The article discusses the development of cancer therapies which would use the immune system, especially CD8+ and CD4+ T cells, to attack malignant cells and destroy tumors. The author discusses the elements of making a cancer vaccine, looking at the identification of antigens, the method of delivery, and at what stage the treatment should be administered. Provenge, a vaccine developed by the pharmaceutical company Dendreon to treat advanced prostate cancer, is examined. Coley's toxin, a bacterial vaccination against cancer developed by the doctor William B. Coley, the immune surveillance theory, suggested by the scientist Paul Ehrlich, and immunotherapy treatments created by Steven Rosenberg at the U.S. National Cancer Institute (NCI) are discussed.

HLA antigen and NK cell activating ligand expression in malignant cells: a story of loss or acquisition

Malignant transformation of cells is often associated with changes in classical and non-classical HLA class I antigen, HLA class II antigen as well as NK cell activating ligand (NKCAL) expression. These changes are believed to play a role in the clinical course of the disease since these molecules are critical to the interactions between tumor cells and components of both innate and adaptive immune system. For some time, it has been assumed that alterations in the expression profile of HLA antigens and NKCAL on malignant cells represented loss of classical HLA class I antigen and induction of HLA class II antigen, non-classical HLA class I antigen and/or NKCAL expression. In contrast to these assumptions, experimental evidence suggests that in some cases dysplastic and malignant cells can acquire classical HLA class I antigen expression and/or lose the ability to express HLA class II antigens. In light of the latter findings as well as of the revival of the cancer immune surveillance theory, a reevaluation of the interpretation of changes in HLA antigen and NKCAL expression in malignant lesions is warranted. In this article, we first briefly describe the conventional types of changes in HLA antigen and NKCAL expression that have been identified in malignant cells to date. Second, we discuss the evidence indicating that, in at least some cell types, classical HLA class I antigen expression can be acquired and/or the ability to express HLA class II antigens is lost. Third, we review the available evidence for the role of immune selective pressure in the generation of malignant lesions with changes in HLA antigen expression. This information contributes to our understanding of the role of the immune system in the control of tumor development and to the optimization of the design of immunotherapeutic strategies for the treatment of cancer.

Metastatic melanoma in the older patient: immunologic insights and treatment outcomes

Cutaneous melanoma (CM) is a highly curable skin cancer of melanocytes if diagnosed early. Unfortunately, its invasion into the deeper dermis increases the risk of it spreading to the lymph nodes and distant organs. Spread of metastatic melanoma (MM) to other organs is among one of the most dangerous conditions that is almost uniformly fatal for the majority of patients with the currently available treatment modalities. Since melanoma is an immunogenic tumor, developing novel immune strategies will continue to play a critical role in designing effective treatment modalities for those at high risk of recurrence and those with distant metastasis. While older age is believed to be a poor prognostic marker for CM, rapid expansion of the aging population and its projected increase in the coming decades is expected to result in a large number of elderly melanoma patients seeking treatment in all stages of disease. This will not only bring with it unique management challenges in this population, but also an increased burden on communities to provide financial and social resources. Comprehensive efforts will need to be directed towards early diagnosis, as well as developing safe and effective treatment. Renewed interest in the cancer immune surveillance theory coupled with recognition of aging-associated weaknesses in the immune system has put the spotlight on immunsenescence as a important risk factor for the rising incidence of CM in the aging population. Comprehensive assessment of the aging immune system might shed light, not only on weaknesses of individual components of the adaptive immune system, but also on the critical imbalances resulting from these weaknesses on anti-melanoma immunity. Identifying these imbalances might help harness novel immune-based treatment of MM in selected elderly patients. This article describes our experience of treating elderly patients with MM and the issues unique to them, with particular emphasis on insights into the aging immune system.

The association of atopic diseases with breast, prostate, and colorectal cancers: a meta-analysis

There is a long-standing interest in finding whether allergic disorders cause or prevent cancer. We meta-analyzed associations of allergies with prostate, breast, and colorectal cancers. We searched MEDLINE, EMBASE, and Web of Science between 1966 and 2008 and eligible reference lists. A total of 16 observational studies were included. Meta-analyses revealed no evidence that asthma, hay fever, or 'any allergy' are associated with cancers of the breast (relative risk, RR = 0.93, 95% CI: 0.73-1.19 for asthma; 1.04, 0.94-1.16 for hay fever; 1.01, 0.94-1.08 for any allergy); prostate (RR = 0.93, 95% CI: 0.76-1.15 for asthma; 0.96, 0.87-1.05 for hay fever; 1.01, 0.87-1.17 for any allergy); or colorectum (RR = 0.95, 95% CI: 0.77-1.16 for asthma; 0.95, 0.86-1.05 for hay fever; 0.94, 0.85-1.04 for any allergy). There was a positive association of atopy (assessed by allergen-specific IgE or skin prick testing) with prostate cancer (RR = 1.43, 95% CI: 1.08-1.91), but not breast (1.18, 0.90-1.55) or colorectal (1.32, 0.69-2.53) cancers. There is little epidemiological support for the immune surveillance theory or antigenic stimulation theory in breast or colorectal carcinogenesis. The findings for prostate cancer warrant further investigation.

Immune selective pressure and HLA class I antigen defects in malignant lesions.

The revived cancer immune surveillance theory has emphasized the active role the immune system plays in eliminating tumor cells and in facilitating the emergence of their immunoresistant variants. MHC class I molecule abnormalities represent, at least in part, the molecular phenotype of these escape variants, given the crucial role of MHC class I molecules in eliciting tumor antigen-specific T cell responses, the high frequency of HLA class I antigen abnormalities in malignant lesions and their association with a poor clinical course of the disease. Here, we present evidence for this possibility and review the potential mechanisms by which T cell selective pressure participates in the generation of tumor cells with MHC class I molecule defects. Furthermore, we discuss the strategies to counteract tumor cell immune evasion.

Dynamic response of cancer under the influence of immunological activity and therapy

The dynamical basis of tumoral growth has been controversial. Many models have been proposed to explain cancer development. The descriptions employ exponential, potential, logistic or Gompertzian growth laws. Some of these models are concerned with the interaction between cancer and the immunological system. Among other properties, these models are concerned with the microscopic behavior of tumors and the emergence of cancer. We propose a modification of a previous model by Stepanova, which describes the specific immunological response against cancer. The modification consists of the substitution of a Gompertian law for the exponential rate used for tumoral growth. This modification is motivated by the numerous works confirming that Gompertz's equation correctly describes solid tumor growth. The modified model predicts that near zero, tumors always tend to grow. Immunological contraposition never suffices to induce a complete regression of the tumor. Instead, a stable microscopic equilibrium between cancer and immunological activity can be attained. In other words, our model predicts that the theory of immune surveillance is plausible. A macroscopic equilibrium in which the system develops cancer is also possible. In this case, immunological activity is depleted. This is consistent with the phenomena of cancer tolerance. Both equilibrium points can coexist or can exist without the other. In all cases the fixed point at zero tumor size is unstable. Since immunity cannot induce a complete tumor regression, a therapy is required. We include constant-dose therapies and show that they are insufficient. Final levels of immunocompetent cells and tumoral cells are finite, thus post-treatment regrowth of the tumor is certain. We also evaluate late-intensification therapies which are successful. They induce an asymptotic regression to zero tumor size. Immune response is also suppressed by the therapy, and thus plays a negligible role in the remission. We conclude that treatment evaluation should be successful without taking into account immunological effects.

Why are dendritic cells central to cancer immunotherapy?

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable alternative to radiation or chemotherapy in the treatment of cancer. The resurgence of interest in cancer immunotherapy reflects the promising results that have been obtained in both animal models and early clinical trials with the DC-based approach. Here I suggest that this optimism is justified because the efficient capture and presentation of antigens by DCs is central to the induction of an immune response. I argue that the mechanism by which DCs capture antigen suggests that the immune system might actually be ‘blind’ to tumours, thereby challenging the theory of immune surveillance.

Immunoaugmentative therapy. An unproven cancer treatment

While it is statistically true that clinical cancer occasionally occurs following development of immune incompetency, the fact remains that the most common forms of cancer (ie, breast, lung, and colon) are not experienced by immunosuppressed individuals. Since there is strong scientific evidence that the unprovoked, normal immune system does not recognize and destroy cancer cells that arise spontaneously, the concept of an immune surveillance system that continuously protects clinically normal humans from cancer remains an appealing but unproven hypothesis. Burton's theory of immune surveillance against cancer appears to be nothing more than a rehash of the hypotheses of many other investigators, embellished with his postulate that four specific anticancer protein factors exist and function in the normal human immune system. The IAT he invented as a treatment for cancer is based on his presumption that he has proven the existence of these factors. But neither his declarations nor those of his proponents offer any objective evidence to support such a conclusion. They have not proven that the IAT components exist or can be extracted from blood without the loss of biologic activity. The tests that are described cannot quantitatively measure the specific IAT proteins and there is no evidence that the IAT fractions possess any immunologic activity. Thus, Burton's tumor antibody has never been shown to be a tumor specific immunoglobulin that can interact with tumor antigens and activate complement. His tumor complement fraction has no complement activity (written communication, G.J. Gray, PhD, June 21, 1984), his blocking protein has not been shown to block anything, his deblocking protein has not been shown to deblock anything, and his human tumor cells have never been shown to lyse following the interaction of tumor antibody and tumor complement. Finally, since there is no information on the quality control procedures being used in the manufacture of the IAT materials, there is the possibility that they may be unsterile and, therefore, hazardous for use in humans. Patients who are considering IAT as treatment for cancer should be made aware of these facts when attempting to reach an informed decision regarding its safety and potential efficacy. While this paper was being reviewed for publication, an IAT proponent newsletter called The Cancer Chronicles published the news that Lawrence Burton died of a heart attack in March 1993. The editor of this newsletter, Ralph Moss, PhD, stated that Burton's clinic would remain open under the direction of its medical director, R. John Clement, MD, and would continue to offer IAT to cancer patients.(ABSTRACT TRUNCATED AT 400 WORDS)

A spontaneous sarcoma dependent on host tumor-specific immune lymphocytes.

The immune surveillance theory postulates that spontaneous tumors are normally rejected by the immune system and appear only when they override host-immune recognition and rejection mechanisms. The present mini-review describes a spontaneous tumor system, the reticulum cell sarcomas (RCS) in SJL/J mice, that is dependent on host tumor-specific immune lymphocytes for growth. This continuous tumor-specific response results in tumor progression and death of the host. This tumor system contradicts the basic concept of immune surveillance. We propose as an explanation that some highly antigenic tumors, like the RCS, may have evolved in a non-autonomous fashion but, nevertheless, have lost regulatory controls of cell proliferation. In the RCS system, the tumor expresses Class II MHC I-E like specificities that are not expressed on the host cells and which selectively stimulate a subpopulation of I-E specific T cells, the V beta 17 a+ clonotype, leading to their expansion and continuous nurturing of the tumor via secreted lymphokines. This neoantigenic stimulation bypasses the tumor regulatory response that might have resulted if the tumor had not expressed neoantigens. Furthermore, passive administration of anti-clonotypic antibody to tumor-bearing mice results in tumor regression and long-term survival through removal of the tumor reactive T cells. Thus, in this tumor system, immunosuppressive treatments are the prescription for tumor rejection.

Biology of Natural Killer Cells

Studies of cytotoxicity by human lymphocytes revealed not only that both allogeneic and syngeneic tumor cells were lysed in a non-MHC-restricted fashion, but also that lymphocytes from normal donors were often cytotoxic. Lymphocytes from any healthy donor, as well as peripheral blood and spleen lymphocytes from several experimental animals, in the absence of known or deliberate sensitization, were found to be spontaneously cytotoxic in vitro for some normal fresh cells, most cultured cell lines, immature hematopoietic cells, and tumor cells. This type of nonadaptive, non-MHC-restricted cellmediated cytotoxicity was defined as “natural” cytotoxicity, and the effector cells mediating natural cytotoxicity were functionally defined as natural killer (NK) cells. The existence of NK cells has prompted a reinterpretation of both the studies of specific cytotoxicity against spontaneous human tumors and the theory of immune surveillance, at least in its most restrictive interpretation. Unlike cytotoxic T cells, NK cells cannot be demonstrated to have clonally distributed specificity, restriction for MHC products at the target cell surface, or immunological memory. NK cells cannot yet be formally assigned to a single lineage based on the definitive identification of a stem cell, a distinct anatomical location of maturation, or unique genotypic rearrangements.

The In Vitro Generation of Effector Lymphocytes and Their Employment in Tumor Immunotherapy

Publisher Summary The theory of immune surveillance against progressive neoplasia has been widely contested in recent years. The doubts casted on its axioms and corollaries have undermined much of the conceptual framework for efforts at tumor immunotherapy, and placed into serious question the validity of continued attempts in this direction. The probable irrelevance of most investigational models in tumor immunology to the natural history of neoplastic disease has been accentuated by the recent findings that signify the inability of neoplasms arising spontaneously in inbred experimental animals to evoke defensive immune reactions. These observations brought about a shift in analogies. Human cancers have come to be considered as analogous, immunologically, to spontaneous tumors of laboratory mice and rats rather than to those that have been the stock in trade of the experimental tumor immunologist. Currently, the climate of opinion regarding the role of immunologic responsiveness in cancer defenses has become pervasively unfavorable. Some investigators still entertain the possibility that immune surveillance may be prominent in the protection against cancers that do not normally come to appearance in nature, but that for those that do, immunologic function is thought to be excluded—as absent or inadequate—from the confrontation.

A model of the role of natural killer cells in immune surveillance--I.

The theory of immune surveillance of Thomas and Burnet stated in part that antigenic differences between neoplastic and normal cells provide the stimulus for their destruction by cells of the immune system. Burnet pointed to the T lymphocyte as the cell which mediated this surveillance. The existence of some form of surveillance in cases of no T lymphocyte functioning presents the possibility that surveillance, if present at all, is mediated by non T cells. Cells identified as naturally cytotoxic killer (NK) cells appear to have properties required of a surveillance effector population. This paper utilizes properties of NK cells and the effects of interferon on this population to construct a mathematical model of the characteristics that an NK cell surveillance would have. A two level theory of immune surveillance is proposed.