Brain cancer immunoediting: novel examples provided by immunotherapy of malignant gliomas

Figures & data

Figure 1. Immunosurveillance hypothesis describes the ability of the immune system to recognize and eliminate tumor cells.

Immunoediting is a process triggered after the encounter between immune components and tumor cells and implies three different outcomes: elimination of cancer cells; equilibrium or immune selection of less immunogenic cancer arising during anti-tumor immune response; escape or expansion of tumor variants resistant to immune reaction.

NK: Natural killer; Treg: Regulatory T cell.

Figure 2. Malignant gliomas avoid recognition by cytotoxic T lymphocytes through loss of major histocompatibility complex class I molecules or exhibit a downmodulation of proteins involved in antigen processing.

Due to the subsequent lack of antigen presentation, a T-cell-mediated immune response is evaded and tumor may become more advanced. Tumor cells can resist apoptosis by downregulating the death receptor. Apart from the defensive mechanisms that tumors use to avoid elimination, several ‘immunosubversion’ (active immunosuppressive) mechanisms against the immune system have also been reported. Tumors may inhibit CD8⁺ T-cell proliferation and promote CD4⁺ T-cell apoptosis by immunosuppressive cytokines and other factors, including TGF-β, IL-10 and prostaglandin E2, which have been reported to inhibit immune function and induce the activation or conversion of immunosuppressive cells, as well as CD4⁺ CD25⁺ Tregs and myeloid-derived suppressive cells.

BBB: Blood–brain barrier; CTL: Cytotoxic T lymphocyte; FasL: Fas ligand; HLA: Human leukocyte antigen; NK: Natural killer; TCR: T-cell receptor.

Figure 3. Different steps of the immune response generated by vaccination, with a peptide representing the specific epitope generated by the most frequent mutation of epidermal growth factor receptor (called EGFRvIII ΔEGFR in the figure).

As shown recently by Sampson et al.[156], the large majority of glioblastomas treated by vaccination were immunoedited and did not show EGFRvIII-positive cells.

DC: Dendritic cell; EGFR: EGF receptor.

Table 1. Factors interfering with recognition and elimination of cancer cells by immune components.

Cancer cells	Immune components
Localization [18,180]	Immune anergy or ignorance [96]
Lack of antigenic peptides or HLA downregulation [44,154]	Lack of tissue homing molecules; defective adhesion [10]
Dysfunction of antigen presentation [26]	Inactivation of T cells within the tumor [48,49]
Release of immunosuppressive factors (IL-10, TGF-β and VEGF) [32–37]	Tregs [54,70,74–76,90]
Tumor counterattack (Fas/FasL) [39,60,61]	T-cell receptor dysfunction [96]
Cannibalization of T lymphocytes [62–64,68]	Induction of anti-peptide but not anti-tumor T cells [156]

Sampson JH, Heimberger AB, Archer GE et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol.28(31), 4722–4729 (2010).

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