New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape

Abstract

The principles of cancer immunoediting have set the foundations for understanding the dual host-protective and tumour sculpting actions of immunity on cancer and establishing the basis for novel individualized cancer immunotherapies. During cancer immunoediting, the host immune system shapes tumour fate in three phases through the activation of innate and adaptive immune mechanisms. In the first phase, Elimination, transformed cells are destroyed by a competent immune system. Sporadic tumour cells that manage to survive immune destruction may then enter an Equilibrium phase where editing occurs. The Escape phase represents the third and final phase of the process, where immunologically sculpted tumours begin to grow progressively, become clinically apparent and establish an immunosuppressive tumour microenvironment. This review focuses on important recent developments that have enhanced our understanding of each phase of the cancer immunoediting process, summarizes the discovery of new predictive and prognostic biomarkers and discusses development of novel and objectively effective cancer immunotherapies.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Number of ‘cancer immunosurveillance or cancer immunoediting’ citations per year demonstrating the importance and increased interest in the field over recent years (derived from search of above terms in ISI Web of Science).

Figure 2

Elimination is a phase of cancer immunoediting where both the innate and adaptive immune system together detect and destroy early tumors before they become clinically visible. Normal cells (blue) are transformed into tumor cells by carcinogens and other genotoxic insults along with the failure of intrinsic tumor suppressor mechanisms (e.g. p53, ATM). These tumor cells express stress-induced molecules such as surface calreticulin, tumor antigens in context of MHC class I molecules, and/or NKG2D ligands recognized by CD8+ effector cells and NK cells, respectively. DCs can also take up and cross-present tumor antigens to T cells including NKT cells (glycolipid antigens presenting via CD1d). These activated effector cells release IFN-γ that can mediate anti-tumor effects by inhibiting tumor cell proliferation and angiogenesis. CD8+ T cells can induce tumor cell apoptosis by interacting with Fas and TRAIL receptors on tumor cells, or by secreting perforin and granzymes. Effector T cells express co-stimulatory molecules such as CD28, CD137, GITR, OX40 that enhance their proliferation and survival. γδ T cells can also recognize and kill tumors expressing NKG2D ligands (MICA/B in humans). Innate immune cells such as macrophages (M1) and granulocytes also contribute to anti-tumor immunity by secreting TNF-α, IL-1, IL-12 and ROS. In the Elimination phase, the balance is towards anti-tumor immunity due to an increase in expression of tumor antigens, MHC class I, Fas and TRAIL receptor on tumor cells and perforin, granzymes, IFN-α/β/γ, IL-1, IL-12, TNF-α in the tumor microenvironment.

Figure 3

In the Equilibrium phase of cancer immunoediting, the immune system holds the tumor in a state of functional dormancy. Some tumor cells undergo genetic and epigenetic changes and due to constant immune pressure, tumor cell variants evolve that resist immune recognition (antigen loss or defects in antigen-presentation) and induce immunosuppression (PDL1). The Equilibrium phase is a balance between anti-tumor (IL-12, IFN-γ) and tumor promoting cytokines (IL-10, IL-23). The adaptive immune system is required to maintain tumor in a functionally dormant state while NK cells and cytokines such as IL-4, IL-17A and IFN-α/β are dispensable.

Figure 4

During the Escape phase of cancer immunoediting, the immune system fails to restrict tumor outgrowth and tumor cells emerge causing clinically apparent disease. In this phase, tumor cells evade immune recognition (loss of tumor antigens, MHC class I or co-stimulatory molecules), express molecules of increased resistance (STAT-3), survival (anti-apoptotic molecule bcl2) and immunosuppression (IDO, TDO, PD-L1, galectin-1/3/9, CD39, CD73, adenosine receptors) and secrete cytokines VEGF, TGF-β, IL-6, M-CSF that enhance angiogenesis. Furthermore, MDSCs, M2 macrophages and DCs may also express immunoregulatory molecules such as arginase, iNOS and IDO and secrete immunosuppressive cytokines IL-10 and TGF-β that can inhibit CD8+ proliferation or induce apoptosis. MDSCs and IDO expressing DCs also induces the generation of regulatory T cells. IDO, arginase, CD39 and CD73 are immunoregulatory enzymes whereas IDO catabolize tryptophan to kyneurenine, arginase catabolize L-arginine to ornithine and urea, CD39 metabolise ATP to AMP which can further be metabolised to adenosine by CD73. Adenosine can bind to adenosine receptors — A2aR and A2bR expressed on tumor cells, endothelial cells and immune cells. T cells including Tregs may express inhibitory receptors such as PD-1, CTLA-4, Tim-3 and LAG-3 that suppresses anti-tumor immune response and favor tumor outgrowth. In the Escape phase, the balance is skewed towards tumor progression due to the presence of immunosuppressive cytokines and molecules such as IL-10, TGF-β, VEGF, IDO, PD-L1.