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The Urgent Need to Recover MHC Class I in Cancers for Effective Immunotherapy


The Urgent Need to Recover MHC Class I in Cancers for Effective Immunotherapy

Federico Garrido et al. Curr Opin Immunol.


Immune escape strategies aimed to avoid T-cell recognition, including the loss of tumor MHC class I expression, are commonly found in malignant cells. Tumor immune escape has proven to have a negative effect on the clinical outcome of cancer immunotherapy, including treatment with antibodies blocking immune checkpoint molecules. Hence, there is an urgent need to develop novel approaches to overcome tumor immune evasion. MHC class I antigen presentation is often affected in human cancers and the capacity to induce upregulation of MHC class I cell surface expression is a critical step in the induction of tumor rejection. This review focuses on characterization of rejection, escape, and dormant profiles of tumors and its microenvironment with a special emphasis on the tumor MHC class I expression. We also discuss possible approaches to recover MHC class I expression on tumor cells harboring reversible/'soft' or irreversible/'hard' genetic lesions. Such MHC class I recovery approaches might well synergize with complementary forms of immunotherapy.


Figure 1
Figure 1
Schematic representation of the evolution of different tumor phenotypes during cancer progression. (a) Tumor rejection phenotype — tumor cells expressing MHC class I molecules (green) surrounded by CD3+, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) inside the tumor. The tumor is rejected and is there is no clinical evidence of the tumor in the majority of cases. (b) Tumor escape phenotype — MHC class I negative tumor cell variants appear. Tumor is heterogeneous containing cells both positive and negative for MHC class I expression. There are infiltrating CD4+ and CD8+ T-lymphocytes at early stages. MHC class I negative cells (red) escape from anti-tumor CD8+ T-cells, and tumor is now composed of only MHC class I negative cells (red). Tumor-specific T-cells remains now at the peritumoral area (stroma) and do not infiltrate tumor mass. (c) Tumor dormant phenotype — MHC class I negative cells within the primary tumor develop unnoticed micrometastases, which maintain an immunological equilibrium. They can survive in a dormant stage for long periods of time. Depletion of CD8, CD4 and asialo GM1 positive cells awakes these cells to progression producing detectable macrometastasis. Interestingly, awaken dormant cells are now positive for MHC class I.

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