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Review
. 2017 Feb;66(2):259-271.
doi: 10.1007/s00262-016-1947-x. Epub 2016 Dec 31.

Rejection versus escape: the tumor MHC dilemma

Federico Garrido  1   2   3 , Francisco Ruiz-Cabello  4   5   6 , Natalia Aptsiauri  5   6
Affiliations
Review

Rejection versus escape: the tumor MHC dilemma

Federico Garrido et al. Cancer Immunol Immunother. 2017 Feb.

Abstract

Most tumor cells derive from MHC-I-positive normal counterparts and remain positive at early stages of tumor development. T lymphocytes can infiltrate tumor tissue, recognize and destroy MHC class I (MHC-I)-positive cancer cells ("permissive" phase I). Later, MHC-I-negative tumor cell variants resistant to T-cell killing emerge. During this process, tumors first acquire a heterogeneous MHC-I expression pattern and finally become uniformly MHC-I-negative. This stage (phase II) represents a "non-permissive" encapsulated structure with tumor nodes surrounded by fibrous tissue containing different elements including leukocytes, macrophages, fibroblasts, etc. Molecular mechanisms responsible for total or partial MHC-I downregulation play a crucial role in determining and predicting the antigen-presenting capacity of cancer cells. MHC-I downregulation caused by reversible ("soft") lesions can be upregulated by TH1-type cytokines released into the tumor microenvironment in response to different types of immunotherapy. In contrast, when the molecular mechanism of the tumor MHC-I loss is irreversible ("hard") due to a genetic defect in the gene/s coding for MHC-I heavy chains (chromosome 6) or beta-2-microglobulin (B2M) (chromosome 15), malignant cells are unable to upregulate MHC-I, remain undetectable by cytotoxic T-cells, and continue to grow and metastasize. Based on the tumor MHC-I molecular analysis, it might be possible to define MHC-I phenotypes present in cancer patients in order to distinguish between non-responders, partial/short-term responders, and likely durable responders. This highlights the need for designing strategies to enhance tumor MHC-I expression that would allow CTL-mediated tumor rejection.

Keywords: Immune escape; MHC class I; PIVAC 15; Tumor rejection; Tumor tissue architecture; Tumor-infiltrating lymphocytes.

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Conflict of interest statement

Authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Different patterns of HLA-I expression in human prostate cancer. Three different HLA-I immunolabeling patterns in prostate tumor tissues: homogeneously positive HLA-I expression, heterogeneous HLA-I staining and homogeneously HLA-I-negative pattern with a clear histological separation of HLA-I-negative tumor from HLA-positive stroma. W6/32 mAb directed against HLA-ABC/B2M complex have been used to characterize tumor tissue HLA-I expression patterns
Fig. 2
Fig. 2
Tissue architecture in HLA-I-positive and HLA-I-negative breast (a), lung (b) and bladder (c) carcinomas in relation with the patterns of tumor infiltration with CD3+ and CD8+ lymphocytes. HLA-I-positive tumor tissue architecture is “permissive,” with tumor infiltration by different mononuclear cells, including T-cells (phase I). At later stages, primary tumors are heterogeneous, composed of HLA-I-positive and HLA-I-negative tumor cells, and TILs. Finally, tumor masses become uniformly HLA-I-negative. Leukocytes and other cells are now located outside the tumor in the stroma with a clear morphological separation of tumor cells from the stroma generating an encapsulated “non-permissive” structure (phase II). W6/32 mAb were used to analyze the expression of HLA-I-ABC/B2M complex
Fig. 2
Fig. 2
Tissue architecture in HLA-I-positive and HLA-I-negative breast (a), lung (b) and bladder (c) carcinomas in relation with the patterns of tumor infiltration with CD3+ and CD8+ lymphocytes. HLA-I-positive tumor tissue architecture is “permissive,” with tumor infiltration by different mononuclear cells, including T-cells (phase I). At later stages, primary tumors are heterogeneous, composed of HLA-I-positive and HLA-I-negative tumor cells, and TILs. Finally, tumor masses become uniformly HLA-I-negative. Leukocytes and other cells are now located outside the tumor in the stroma with a clear morphological separation of tumor cells from the stroma generating an encapsulated “non-permissive” structure (phase II). W6/32 mAb were used to analyze the expression of HLA-I-ABC/B2M complex
Fig. 3
Fig. 3
HLA-I immunostaining patterns in primary melanoma (a) and colorectal tumor (b) and in corresponding autologous metastases. a Primary melanoma lesion has heterogeneous HLA-I labeling pattern with positive and negative areas surrounded by stroma. Autologous melanoma metastasis is uniformly negative for HLA-I expression, while the stroma is HLA-I-positive. b Primary colorectal cancer is clearly heterogeneous for HLA-I expression with positive and negative areas, while autologous liver metastasis is homogeneously HLA-I-negative
Fig. 4
Fig. 4
HLA-I-negative tumors encapsulated by surrounding fibrous stroma. a Breast carcinoma homogeneously negative for HLA-I with a clear separation from HLA-I-positive stroma surrounding tumor nests. CD3+ cells are outside the tumor tissue in the fibrous stromal capsule. b The “non-permissive” tumor tissue structure observed in HLA-I-negative tumors (lung, colorectal, laryngeal, bladder). HLA-I-negative tumor markedly contrasts with the HLA-I-positive stroma. Note that these tumor tissue examples represent primary lesions with a homogeneous negative HLA-I pattern. Tissue architecture with tumor nodes encapsulated by the stroma is clearly observed. W6/32 mAb were used to analyze the expression of HLA-I-ABC/B2M complex
Fig. 5
Fig. 5
Three-dimensional schematic demonstration of the two phases of tumor development with the corresponding tissue organization patterns: a phase I or “permissive” and b phase II or “non-permissive/encapsulated”. a In phase I, tumor cells are HLA-I-positive (green) and are surrounded and killed by CD8+ T lymphocytes (yellow). HLA-I-negative or HLA-I-deficient tumor cells (red) escape the recognition and destruction by TILs. The tumor is now heterogeneous and is composed of HLA-I-positive and HLA-I-negative cells. Cells other than T-cell tumor-infiltrating cells, such as macrophages (blue), can also be found within the tumor tissue. This pattern of the tumor/stroma tissue architecture is “permissive,” since it permits leukocytes and other cells to get in close contact with tumor cells. b In phase II as a result of T-cell immune selection, the tumor becomes homogeneously negative for HLA class I expression (red cells). These HLA-I-negative tumor cells are encapsulated by the stroma rich in tumor-specific T lymphocytes (yellow) and other cells (blue), such as Tregs and MDSCs. A clear physical separation between these two structures (tumor cells and the stroma) creates a “non-permissive” tissue structure which prevents immune cell infiltration into the tumor mass. Thus, due to this immunosuppressive tumor microenvironment, HLA-I-negative cells are in an immune privileged tumor structure
Fig. 6
Fig. 6
Frequency of HLA-I loss in different types of cancer. Summarized results of the immunohistological analysis of tumors using different antibodies directed against monomorphic, locus and allele-specific HLA determinants. For details, see Refs. [21, 22, 29, 39, 65, 67]
Fig. 7
Fig. 7
Recovery of HLA-I expression in melanoma cells: by IFN in the case of “soft” lesions and by adenovirus-mediated B2M gene transfer in cells with “hard” HLA-I lesions. a “soft” lesions—a selective HLA-B locus downregulation in ESTDAB-25 cells and total HLA-ABC downregulation in ESTDAB-42 cells—are corrected by IFN-γ (as demonstrated on flow cytometry plots); b resistance to IFN-γ-mediated HLA-ABC upregulation in melanoma cell line ESTDAB-004 (“hard” lesion); c recovery of HLA-I expression in melanoma cells with total loss of HLA-I expression due to B2M mutations (“hard” lesion) after adenovirus-mediated transfer of a wild-type human B2M gene (as demonstrated by confocal microscopy). W6/32 mAB were used to examine cell surface HLA-ABC/B2M complex; L368 mAb were used to detect B2M protein
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