Immunological Approaches Towards Cancer and Inflammation: A Cross Talk

Abstract

The inflammation is the protective response of the body against various harmful stimuli; however, the aberrant and inappropriate activation tends to become harmful. The acute inflammatory response tends to resolved once the offending agent is subside but this acute response becomes chronic in nature when the body is unable to successfully neutralized the noxious stimuli. This chronic inflammatory microenvironment is associated with the release of various pro-inflammatory and oncogenic mediators such as nitric oxide (NO), cytokines [IL-1β, IL-2, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)], growth factor, and chemokines. These mediators make the inflammatory microenvironment more vulnerable toward tumorigenesis. The pro-inflammatory mediators released during the chronic inflammation tends to induce several molecular signaling cascades such as nuclear factor kappa B, MAPKinase, nuclear factor erythroid 2-related factor 2, phosphoinositide-3-kinase, Janus kinases/STAT, Wnt/B-catenin, and cyclic AMP response element binding protein. The immune system and its components have a pleiotropic effect on inflammation and cancer progression. Immune components such as T cells, natural killer cells, macrophages, and neutrophils either inhibit or enhance tumor initiation depending on the type of tumor and immune cells involved. Tumor-associated macrophages and tumor-associated neutrophils are pro-tumorigenic cells highly prevalent in inflammation-mediated tumors. Similarly, presence of T regulatory (Treg) cells in an inflammatory and tumor setting suppresses the immune system, thus paving the way for oncogenesis. However, Treg cells also inhibit autoimmune inflammation. By contrast, cytotoxic T cells and T helper cells confer antitumor immunity and are associated with better prognosis in patients with cancer. Cytotoxic T cells inflict a direct cytotoxic effect on cells expressing oncogenic markers. Currently, several anti-inflammatory and antitumor therapies are under trials in which these immune cells are exploited. Adoptive cell transfer composed of tumor-infiltrating lymphocytes has been tried for the treatment of tumors after their ex vivo expansion. Mediators released by cells in a tumorigenic and inflammatory microenvironment cross talk with nearby cells, either promoting or inhibiting inflammation and cancer. Recently, several cytokine-based therapies are either being developed or are under trial to treat such types of manifestations. Monoclonal antibodies directed against TNF-α, VEGF, and IL-6 has shown promising results to ameliorate inflammation and cancer, while direct administration of IL-2 has been shown to cause tumor regression.

Keywords: T cytotoxic cells; T helper cells; cancer; cytokines; immune system; inflammation; tumor-associated macrophages; tumor-associated neutrophils.

Figure 1

Various intrinsic and extrinsic factors trigger the recruitment of the inflammatory cells to the site of inflammatory insult, with resultant activation of several molecular signaling cascades. This signaling cascades are associated with increased production of inflammatory cytokines and the hence the establishment of inflammation. This inflammation is either of acute nature and resolved or is of chronic nature. The chronic form of inflammation is associated with cancer initiation.

Figure 2

Whenever there is any inflammatory stimulus to the cell, there is activation of several molecular cascades such as NF-κB, Nrf2, MAPKinase, JAK/STAT, p53, PI3K/mTOR, CREB, and Wnt/Beta catenin. The appropriate activation of these molecular cascades is associated with the resolution of inflammation; however, inappropriate activation of such pathway causes persistent and chronic inflammation followed by tumor initiation, progression, invasion, and metastasis. NF-κB, nuclear factor-κB; Nrf2, nuclear factor erythroid 2-related factor 2; MAPKinase, mitogen-activated protein kinases; JAK/STAT, Janus kinases/signal transducing and activation of transcription; p53, transformation-related protein 53; PI3K/mTOR, phosphoinositide-3-kinase; CREB, cyclic AMP response element binding protein.

Figure 3

Once the chronic inflammatory microenvironment is established and trigger the initiation of cancer, then the cancer undergoes various stages such as proliferation, promotion, metastasis, and angiogenesis under the influence of various cytokines.