The interplay between innate and adaptive immunity regulates cancer development

Abstract

There is increasing clinical and experimental evidence that inflammation and cancer are causally linked. Much progress has been made in understanding how inflammatory cells contribute to cancer development; however, it is still largely unknown which molecular mechanisms are responsible for initiation and maintenance of chronic inflammation associated with developing neoplasms. This review will discuss how the adaptive and innate immune systems interact during physiological and chronic inflammation, with a focus on studies revealing new insights into the role of adaptive immune cells as important regulators of chronic inflammation-associated carcinogenesis. We will speculate on whether current knowledge about the dysregulated interplay between adaptive and innate immunity during chronic inflammatory disorders might be useful in understanding and targeting the underlying mechanisms of chronic inflammation-associated neoplastic progression.

Fig. 1

Schematic representation of the interplay between innate and adaptive immunity. The immune system can be divided into two subsets, the innate immune system, also referred to as the first line of immune defense against infection, and the adaptive immune system. The innate immune system consists of macrophages, granulocytes (neutrophils, basophils, and eosinophils), natural killer cells (NK cells), mast cells, dendritic cells (DCs), and soluble factors, e.g., complement components. The adaptive immune system consists of T and B lymphocytes and antibodies. NK T cells and γδ T cells are present at the intersection between adaptive and innate immunity. Crosstalk between the two branches of the immune system is mediated by complex interactions between cells of both immune subsets and their soluble factors. The innate immune system regulates adaptive immune responses by the production of cytokines, interaction between DCs and lymphocytes, and activation of the complement system. The adaptive immune system modulates innate immune responses by cytokine and antibody production

Fig. 2

Model of the potential role of the adaptive immune system in the enhancement of chronic inflammation-associated epithelial tumorigenesis. Antigens present in early neoplastic lesions are transported to lymphoid organs by dendritic cells and trigger adaptive immune responses. Subsequent dysregulated interactions between adaptive and innate immunity can result in excessive activation of the innate immune system, resulting in chronic inflammatory states in the neoplastic microenvironment. Activated innate immune cells promote tumor development via several mechanisms. Inflammatory cells are capable of modulating expression of genes within neoplastic cells, e.g., NF-κB, that regulate cell cycle and survival. Inflammatory cells regulate angiogenesis by the production of proangiogenic mediators, such as VEGF-A in neoplastic tissues. In addition, infiltrating inflammatory cells indirectly contribute to tumor development by the production of extracellular proteases, e.g., MMPs. MMPs regulate neoplastic progression by remodeling ECM components as well as non-ECM substrates such as cytokines, growth factors, cell–cell and cell-matrix adhesion molecules, and thus contribute to angiogenesis, inflammation and proliferation.