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Rejection versus escape: the tumor MHC dilemma

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Abbreviations

APM:

Antigen presentation machinery

B2M:

Beta-2-microglobulin

BCG:

Bacille Calmette–Guerin

CTL:

Cytotoxic T lymphocyte

CTLA4:

Cytolytic T lymphocyte-associated antigen 4

DNA:

Deoxyribonucleic acid

FACS:

Fluorescence-activated cell sorter/sorting

FITC:

Fluorescein isothiocyanate

HLA:

Human leukocyte antigen

IFN:

Interferon

IL:

Interleukin

LOH:

Loss of heterozygocity

mAb:

Monoclonal antibodies

MDSC:

Myeloid-derived suppressor cell

MFI:

Mean fluorescence intensity

MHC:

Major histocompatibility complex

PCR:

Polymerase chain reaction

TH1:

T helper 1

TIL:

Tumor infiltrating lymphocyte

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Acknowledgements

The authors would like to thank Dr. Teresa Rodriguez for helping in the design of the figures, Dr. Monica Bernal and Francisco Perea for providing some immunohistological images and Carlos Bandeira for designing Fig. 5.

Grant support

This work was supported by Grants from the Instituto de Salud Carlos III co-financed by FEDER funds (European Union) (PI 11/1022, PI 11/1386, PI14/1978, PI16/00752‚ RETIC RD 06/020, RD09/0076/00165, PT13/0010/0039) and Junta de Andalucía in Spain (Group CTS-143, PI09/0382).

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Authors and Affiliations

  1. Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Av. Fuerzas Armadas s/n, Granada, Spain

    Federico Garrido & Francisco Ruiz-Cabello

  2. Instituto de Investigación Biosanitaria ibs.Granada, Granada, Spain

    Federico Garrido, Francisco Ruiz-Cabello & Natalia Aptsiauri

  3. Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain

    Federico Garrido, Francisco Ruiz-Cabello & Natalia Aptsiauri

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  1. Federico Garrido
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  2. Francisco Ruiz-Cabello
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  3. Natalia Aptsiauri
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Correspondence to Federico Garrido.

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This paper is a Focussed Research Review based on a presentation given at the Fifteenth International Conference on Progress in Vaccination against Cancer (PIVAC 15), held in Tübingen, Germany, 6th – 8th October, 2015. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews and meeting report.

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Garrido, F., Ruiz-Cabello, F. & Aptsiauri, N. Rejection versus escape: the tumor MHC dilemma. Cancer Immunol Immunother 66, 259–271 (2017). https://doi.org/10.1007/s00262-016-1947-x

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