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.

(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.

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.

(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.