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Review
. 2002 Nov;3(11):999-1005.
doi: 10.1038/ni1102-999.

Natural selection of tumor variants in the generation of "tumor escape" phenotypes

Hung T Khong  1 , Nicholas P Restifo
Affiliations
Review

Natural selection of tumor variants in the generation of "tumor escape" phenotypes

Hung T Khong et al. Nat Immunol. 2002 Nov.

Abstract

The idea that tumors must "escape" from immune recognition contains the implicit assumption that tumors can be destroyed by immune responses either spontaneously or as the result of immunotherapeutic intervention. Simply put, there is no need for tumor escape without immunological pressure. Here, we review evidence supporting the immune escape hypothesis and critically explore the mechanisms that may allow such escape to occur. We discuss the idea that the central engine for generating immunoresistant tumor cell variants is the genomic instability and dysregulation that is characteristic of the transformed genome. "Natural selection" of heterogeneous tumor cells results in the survival and proliferation of variants that happen to possess genetic and epigenetic traits that facilitate their growth and immune evasion. Tumor escape variants are likely to emerge after treatment with increasingly effective immunotherapies.

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Figures

Figure 1
Figure 1. Activation versus suppression during tumor progression
Immune activation during early tumor progression may be triggered by the expression of neoantigens. In addition, the progressive growth of tumors may be associated with the invasion and destruction of surrounding normal tissues. Other factors that may cause immune activation include generation of heat shock proteins (Hsps), which result from cellular stress, and ROS such as OH− and H2O2. Conversely, immune activation and function may be hampered by a lack of appropriate costimulation, the presence of immunosuppressive cytokines (for example, VEGF, IL-10 and TGF-β), and the impact of immunoregulatory cells such as CD4+CD25+ T cells and NKT cells. As tumors grow, these events occur in the presence of massive apoptosis and necrosis of tumor cells, infiltrating immune cells and surrounding stromal cells. The fate of tumors may be dictated by the net effect of immune activation and immune inhibition.
Figure 2
Figure 2. Natural selection of tumor variants in the generation of “tumor escape” phenotypes
(a) Genomic instability gives rise to genetic diversity in tumors. Natural selection of tumor variants occurs by differential propagation of tumor subclones in their microenvironment. (b) The same concept also applies to tumor growth after effective immunotherapy.
Figure 3
Figure 3. Molecular mechanisms responsible for HLA class I deficiency
Tumor antigens are processed in the proteosome and generate peptides that are transported by TAP to the endoplasmic reticulum (ER); there they bind to certain HLA class I heavy chain in association with β2-microglobulin. The peptide-HLA complexes are then transported through the Golgi to the cell surface. Several different defects are associated with tumor “escape” from immune recognition: (a) defects in components of the antigen-processing machinery (such as LMP-2 and LMP-7) in the proteosome result in HLA class I down-regulation; (b) defects in peptide transporters TAP-1 or TAP-2 cause HLA class I down-regulation; and (c) LOH on chromosome 6 causes HLA class I haplotype loss. Defects in the transcriptional regulation of the HLA class I gene result in HLA class I locus loss. Point mutations or gene deletions involving the HLA class I heavy chain result in HLA class I allelic loss. (d) β2-microglobulin (β2M) mutation or deletion results in total loss of HLA class I.
Figure 4
Figure 4. Alternative models for the induction of FasL-mediated T cell death after encounter with tumor cells
(a) AICD of T cells after recognition of tumor cells. Tumor recognition leads to activation of T cells and up-regulation of Fas and FasL on T cell surface, which results in the T cell killing of itself (“suicide”) and of other T cells (“fratricide”). (b) Proposed tumor “counterattack” model. Tumor cells express functional FasL and kill infiltrating Fas-expressing T cells via Fas-FasL binding, which leads to tumor escape. However, ligation of Fas expressed on innate immune cells such as neutrophils, macrophages and immature DCs by FasL expressed on tumor cells may also lead to release of multiple proinflammatory cytokines and chemokines, setting the stage for tumor rejection.
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