Alpha1-antitrypsin, an endogenous immunoregulatory molecule: distinction between local and systemic effects on tumor immunology

Abstract

The acute-phase protein α1-antirypsin (AAT) has recently been suggested to exert beneficial effects in various immune-associated pathologies, such as graftversus-host disease, rheumatoid arthritis, multiple sclerosis and allogeneic transplantation. These effects have been demonstrated to take place through direct immunomodulation of dendritic cells, macrophages, neutrophils and B cells, while allowing, in a yet inexplicable distinction, intact isolated functions of T cells and NK cells. With such a unique discriminatory targeting of immunocytes, AAT drives immune responses simultaneously towards regulation of inflammation and expansion of antigen-specific regulatory T cells (Tregs). Based on this intriguing activity profile, a concern was raised regarding the impact of chronic treatment with human AAT with respect to susceptibility to tumors and to metastatic spread. Tumor development is linked to inflammatory responses in a manner which largely promotes immune evasion. Local innate immunocytes, such as tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs) and the recently appreciated tumor-associated neutrophils (TANs), are considered instrumental in primary tumor survival. This is accomplished in part by the release of growth factors and cytokines, including VEGF, TGFβ, IL-10 and IL-1 receptor antagonist (IL-1Ra), all of which have been demonstrated to be elevated in inflammatory conditions during AAT therapy. While clinical studies report heightened serum AAT levels in patients with a variety of advanced tumors, there is no evidence to point to a particular pro-tumor effect of AAT, and the possibility that its elevation in the blood might represent a meresystemic marker-rather than an accessory to tumor development-is grossly overlooked. Indeed, preclinical studies reveal significant inhibition of tumor development during treatment with AAT, and prolonged follow-up studies of individuals who receive life-long excessive doses of intravenous AAT do not depict a rise in tumor occurrence. Considering the prospect of AAT being indicated for medical indications to individuals with normal levels of the protein, its relation to tumor immunology is of immense importance. We hereby review the current knowledge regarding some possible roles that AAT may play, both locally and systemically, in the delicate and detrimental arena of tumor immunology.

A Novel Strategy to Investigate Tissue‐Secreted Tumor Microenvironmental Proteins in Serum toward Development of Breast Cancer Early Diagnosis Biomarker Signature

“…TGF‐β and IL‐6 expression promotes tumor progression, recurrence, and immune evasion. A1AT inhibits the ECM degradation and extravasation by inhibiting the environment created by tumor‐associated macrophages and tumor‐associated neutrophils (TANs) and also downregulates the expression of IL‐6, TNF‐α, and IL‐1β to the tumor periphery . It is reported by many studies that this tumor suppressor ability of A1AT is lost in cancer cells by downregulating its expression.…”

Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution

“…It is an acute phase protein that increases its concentration up to 5-fold when the body is injured or infected. Recent research shows that A1AT has anti-inflammation, anti-protease, immunomodulation, cytoprotective, and pro-angiogenic activities 28,29,38,[30][31][32][33][34][35][36][37] . It selectively inhibits neutrophil recruitment and cytokine production and neutralizes many proinflammatory cytokines 36,[39][40][41][42][43][44][45][46] .…”

“…A1AT is an acute-phase protein whose concentration increases five-fold when the body is injured or infected. A1AT has anti-inflammatory, anti-protease, pro-resolution, cytoprotective, and pro-angiogenic properties 78–88 . It selectively inhibits neutrophil recruitment and cytokine production and neutralizes many pro-inflammatory cytokines 87,89–96 .…”

“…It selectively inhibits neutrophil recruitment and cytokine production and neutralizes many pro-inflammatory cytokines 87,89–96 . It suppresses M1 macrophages while promoting M2 macrophages and Treg cells 78 , 97–104 . It also reduces bacterial and viral burden 105–113 .…”

“…A1AT has anti-inflammatory, anti-protease, pro-resolution, cytoprotective, and proangiogenic properties [78][79][80][81][82][83][84][85][86][87][88] . It selectively inhibits neutrophil recruitment and cytokine production and neutralizes many pro-inflammatory cytokines 87,[89][90][91][92][93][94][95][96] .…”