MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

Abstract

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.

Identification and Validation of Prognostic Related Hallmark ATP-Binding Cassette Transporters Associated With Immune Cell Infiltration Patterns in Thyroid Carcinoma

“…The VEGF-KDR signaling pathway was found to play an immunosuppressive role in TME and immune effector cell activity ( 76 ). MHC molecule expression is known to mediate immune escape mechanisms in tumors ( 77 ). VTCN1, also termed B7-H4, reportedly inhibits T cell proliferation and cytokine secretion, thereby negatively regulating T cell immune response, and positively regulating immune escape ( 78 ).…”

Igniting Hope for Tumor Immunotherapy: Promoting the “Hot and Cold” Tumor Transition

“… 88 (2) Natural killer cell therapy restores MHC-I levels; NK cells identify and remove cells with downregulated or absent MHC-I expression by releasing cytotoxic particles or binding TNF receptor superfamily death receptors on target cells to ligands expressed by NK cells. 48 For example, in patients with periampullary adenocarcinoma, pancreatic adenocarcinoma, and non–small cell lung cancer, significant infiltration of NK cells often correlates with a better outcome. 89 , 90 (3) Increased expression of IFN-γ to restore tumor MHC-I levels: interferon activates the JAK/STAT pathway, which phosphorylates and dimerizes the STAT that is present in an inactive form in the envelope and acquires a migratory invasive phenotype, which then upregulates the expression of MHC-I.…”

“… 89 , 90 (3) Increased expression of IFN-γ to restore tumor MHC-I levels: interferon activates the JAK/STAT pathway, which phosphorylates and dimerizes the STAT that is present in an inactive form in the envelope and acquires a migratory invasive phenotype, which then upregulates the expression of MHC-I. 48 Meanwhile, IFN-γ can also induce NLRC5 expression to further form CITA enhancers and induce an increase in MHC-I expression. 86 (4) Inhibition of autophagy restores MHC-I levels: although downregulation of MHC-I expression is frequently observed in most malignancies (eg, pancreatic ductal adenocarcinoma [PDAC]), 86 gene mutations leading to MHC class I deficiency have rarely been reported.…”

“…Moreover, decreased levels of interferon-γ (IFN-γ) in cancer cells can also lead to the downregulation of MHC-I. 50 , 51 NLRC5 is a crucial modulator of IFN-γ that upregulates MHC-I expression; 48 and lower NLRC5 activity is closely correlated with MHC-I downregulation and can result in immune evasion. 52 Mutations in oncogenes are also critical for the downregulation of MHC-I.…”

CTLA-4 Facilitates DNA Damage–Induced Apoptosis by Interacting With PP2A

“…Immune cells undergo apoptosis or lose their function during cancer therapy—problems that urgently require a solution. Immunotherapy, also known as immune checkpoint blockade, is currently one of the most exciting and promising modalities of investigation and development in the field of cancer therapy, and T cells play central roles in cancer immunotherapy ( Shklovskaya and Rizos, 2021 ). Cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) is an immunoregulatory molecule found on T cells and a negative regulator of T-cell activation ( Teft et al, 2006 ).…”