Autoimmunity‐mediated antitumor immunity: Tumor as an immunoprivileged self

Abstract

IntroductionA cardinal capacity of the immune system is to differentiate between "self", the body's own tissue, and "non-self", exemplified by microbial infectious agents. Malignant tumor tissues present a distinct challenge to the immune system as "altered self".Correspondence: Dr. Zhibin Chen e-mail: zchen@med.miami.edu Antigenic proteins from mutated genes in cancer cells, or viral products from transformed tumor cells, may trigger the immune system as tumor-specific antigens (TSAs) that are not expressed by nonmalignant tissues. However, for the vast majority of tumors, TSA have yet to be identified. Well-studied tumor-associated antigens (TAAs) are in fact self antigens associated with cellular differentiation [1].The difficulty to identify TSA compels a supposition that cancer cells are largely "self". The premise of cancer cells as "altered self" would predict the well-recognized association of autoimmune risk with cancer immunotherapy [2]. On the other hand, the "altered C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 2584-2596 Cellular immune response 2585 self" view could also foretell autoimmunity as a beneficial effector to destroy cancer cells. In other words, although autoimmunity and tumor immunity are often viewed as being on opposite sides of the same coin, they could also be viewed to be on the same side of the coin, serving as overlapping mechanisms for tumor destruction. Indeed, the remarkable benefits of cancer immunotherapies showed in recent immunotherapy trials, most notably anti-CTLA4 antibody blockade, often came with the price of autoimmune adverse effects [3]. The intricate tangle of auto-immune toxicity and antitumor immunity substantially affects the benefit/risk ratio calculation in immunotherapies [1]. On the other hand, autoimmunity may serve to benefit clinical management of cancers. Evidence gathered from the clinics treating a variety of cancers with immunotherapies based on IL-2 [4], interferon α-2b [5], or CTLA4 [3,6] suggests that the therapy-induced autoimmunity, at least in part, may actually mediate the destruction of cancer cells. The clinical observations provoke suggestion of a paradigm shift, to which autoimmunity is not a shunned side effect, but instead an acceptable or even desirable antitumor mechanism [7]. However, it is still not well understood how self-antigen-specific T cells target tumor versus healthy tissues, and how they are regulated in tumor settings.A variety of immune suppressive mechanisms have been implicated in cancers. In the adaptive branches, Treg cells and CTLA4 are among the most prominent cellular and molecular inhibitors. Treg cells depend on CTLA4 for function [8]. CTLA4 is constitutively expressed on Treg cells but is also induced in activated Teff cells. Conditional knockout experiments indicated that CTLA4 functions predominantly through Treg cells [8]. However, other studies with CTLA4 knockout models or antibody blockade indicate that CTLA4 regulates Teff cells intrinsically and through...

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“…PL4 (Chen et al, 2006), OT1 (Hogquist et al, 1994), RIP-mOVA (Kurts et al, 1996), MIP-CFP (Hara et al, 2006) and CAG-CFP (Hadjantonakis et al, 2002) transgenic lines were described previously. The CTLA4shRNA and PL4 lines were backcrossed onto B6 background for >10 generations (Miska et al, 2012). The CTLA4shRNA transgene caused 2-3-fold reduction in CTLA4 expression.…”

“…The CTLA4shRNA transgene caused 2-3-fold reduction in CTLA4 expression. The stability of the RNAi effect in the transgenic lines on different genetic background has been established (Chen et al, 2006;Miska et al, 2012). FIR (Foxp3-IRIS-RFP knock-in) mice (Wan and Flavell, 2005) were backcrossed onto the NOD background for 10 generation to create the NOD.Foxp3 FIR line.…”

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