Rejection versus escape: the tumor MHC dilemma

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


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Immunotherapy
  • Neoplasms / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Escape / immunology*


  • Histocompatibility Antigens Class I