Roles of the immune system in cancer: from tumor initiation to metastatic progression

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Roles of the immune system in cancer: from tumor initiation to metastatic progression


Abstract

The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.

Keywords: disseminated tumor cells, tumor-associated macrophages, metastasis-associated immune cells, patient-derived xenograft, immune cross-talk, cancer heterogeneity

The primary effector cell of innate immunity; the first responders of the immune system. ... Cytotoxic T cells are the primary effector cells of adaptive immunity. Activated cytotoxic T cells can migrate through blood vessel walls and non-lymphoid tissues. They can also travel across the blood brain barrier.

https://www.healio.com/hematology-oncol ... une-system

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169832/

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* effector cells


“In the immune system, effector cells are the relatively short-lived activated cells that defend the body in an immune response. ... Effector B cells are called plasma cells and secrete antibodies, and activated T cells include cytotoxic T cells and helper T cells, which carry out cell-mediated responses.”

https://www.britannica.com/science/effector-cell

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“Cancer remains a major cause of death worldwide, and, with an aging population, its annual toll of 8.2 million is only expected to increase (Ferlay et al. 2015). In this respect, carcinomas can be broadly divided into two groups: metastatic (the principal cause of cancer-related deaths) and nonmetastatic (Siegel et al. 2016). Traditionally, metastasis has been considered to occur in later stages of cancer progression; however, accumulating evidence has also described metastatic dissemination during early tumor formation (Hosseini et al. 2016). During metastasis, disseminating cancer cells escape from primary tumors and acquire cellular traits that allow them to travel and colonize distant organs (Chambers and Werb 2015; Lambert et al. 2017; Gonzalez et al. 2018).

Primary and metastatic tumors are complex ecosystems composed of neoplastic cells, extracellular matrix (ECM), and “accessory” nonneoplastic cells, which include resident mesenchymal support cells, endothelial cells, and infiltrated inflammatory immune cells. Cross-talk between cancer cells and accessory cells fuels and shapes tumor development. During tumor formation, the tissue architecture evolves into a highly specialized microenvironment characterized by a corrupted ECM and chronic inflammation (Coussens and Werb 2002).

Cancer-associated inflammation, which is present at different stages of tumorigenesis, contributes to genomic instability, epigenetic modification, induction of cancer cell proliferation, enhancement of cancer anti-apoptotic pathways, stimulation of angiogenesis, and, eventually, cancer dissemination (Hanahan and Weinberg 2011). Studies during the last two decades have demonstrated that inflammatory immune cells are essential players of cancer-related inflammation. Efforts have focused on understanding how immune cells impact tumor fate in different stages of disease: early neoplastic transformation, clinically detected tumors, metastatic dissemination, and therapeutic intervention. In this review, we focus on recent results, unifying concepts, limits, and futures challenges in studying cancer-associated inflammatory cells, with an emphasis on metastatic carcinomas.“

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“Cancer-related inflammatory conditions

Since 1863, when Virchow first hypothesized that cancer develops as the product of unresolved inflammation (Balkwill and Mantovani 2001), tumor-associated inflammation has been key to shaping our modern understanding of cancer progression (Fig. 1). Today, it is accepted that chronic inflammation is a critical hallmark of cancer, with at least 25% of cancers associated with it (Hussain et al. 2000; Coussens and Werb 2002; Beaugerie et al. 2013), and possible underlying causes include microbial infections, autoimmunity, and immune deregulation. For example, human papilloma viruses (HPVs) induce inflammation and are responsible for 90%–100% of all cervical cancers (Bosch et al. 2002). Similarly, chronic infection with Helicobacter pylori elevates the risk for gastric cancer (Hussain et al. 2000). In addition, the immune deregulation seen in inflammatory bowel disease increases colorectal cancer incidence (Lakatos and Lakatos 2008). The nonhuman form of sialic acid—N-glycolylneuroaminic acid (Neu5Gc)—in red meat can be incorporated into human tissue and recruit inflammatory cells (Samraj et al. 2015). In this sense, diet may play a causal role in induction of cancer-associated inflammation (Gupta et al. 2010). Importantly, tobacco and obesity, both of which induce low-grade inflammation, give rise to elevated risks of cancer (Howe et al. 2013); this evidence suggests that the majority of cancers is associated with unresolved inflammation.“

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Abstract

Innate and adaptive immune system cells play a major role in regulating the growth of cancer. Although it is commonly thought that an immune response localized to the tumor will inhibit cancer growth, it is clear that some types of inflammation induced in a tumor may also lead to cancer proliferation, invasion, and dissemination. Recent evidence suggests, however, that some patients with cancer can mount an antitumor immune response that has the potential to control or eliminate cancer. Indeed, a so-called “immune response” signature has been described in malignancy that is associated with improved outcomes in several tumor types. Moreover, the presence of specific subsets of T cells, which have the capability to penetrate tumor stroma and infiltrate deep into the parenchyma, identifies patients with an improved prognosis. Immune-based therapies have the potential to modulate the tumor microenvironment by eliciting immune system cells that will initiate acute inflammation that leads to tissue destruction.

INTRODUCTION

Cancer is an inflammatory disease. The types of immune system cells that are found infiltrating human malignancy are varied and consist of cells of the innate immune system (eg, macrophage, neutrophils) as well as cells associated with an adaptive immune response (eg, T and B cells). Innate immunity represents the body's “gut reaction” to an abnormality, such as cancer, and does not involve specific recognition of immunogenic proteins, which are called antigens. Adaptive immunity is a specific response to a particular tumor-associated antigen. Both innate and adaptive immune cells orchestrate an inflammatory environment that may function to either stimulate or inhibit cancer growth.(Table 1). It is suggested that the inflammatory response found in many cancers is one of chronic inflammation, resulting in an environment rich in innate immune cells, which secrete substances that promote angiogenesis and cell proliferation. The growth-enhancing properties of this type of inflammatory response have been likened to inflammation consistent with wound healing.1 Increasing evidence, however, indicates that some patients with cancer mount an adaptive immune response specifically directed against antigenic proteins expressed in their tumors. T cells that secrete cytokines such as interferon gamma (IFN-γ) generate acute inflammation that results in expansion of cytotoxic T cells (CTLs), tissue destruction, and the potential control or even elimination of cancer.2 The tissue-destructive properties of this type of inflammatory response are consistent with what would be operative in acute allograft rejection. The clinical application of immune-based cancer therapeutics requires strategies that will elicit a tumor-specific acute inflammatory response that induces tumor rejection. The cancer must appear dangerous enough for the immune system to initiate a tissue- destructive response.3

The immune response is broken down into innate immunity, which an organism is born with, and adaptive immunity, which an organism acquires following disease exposure.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041789/