Content area
Full Text
The success of tumor immunotherapy, while partial, confirms the existence and importance of tumor immunosurveillance. CD8+ T cell recognition of tumor-specific peptides bound to MHC class I (MHC-I) molecules is central to this process. In this issue of the JCI, Fang, Wang, et al. describe a unique tumor immunoevasion strategy based on endocytosis and degradation of MHC-I complexes mediated by the trafficking factor MAL2. Notably, MAL2 expression was associated with poor prognosis of breast cancer, and its downregulation enhanced CD8+ T cell recognition of breast cancer in various experimental models. This work demonstrates that a deeper understanding of tumor interference with MHC-I stability and trafficking has considerable potential for enhancing immunotherapies.
Tumor immunosurveillance and evasion
Tumor immunoevasion is a multifaceted process encompassing expression of immune checkpoints, cytokine production in the tumor microenvironment, and impaired innate and adaptive immune detection of malignant cells. The recent explosion of successful immunotherapies places antigen processing and presentation center stage in T cell-mediated immunosurveillance. Nearly all nucleated cells express MHC class I (MHC-I). By presenting small peptides derived from endogenous proteins, MHC-I enables CD8+ T cells to surveil foreign and abnormal translation products, including viral proteins and tumor-associated antigens.
The principal elements of the MHC-I antigen processing pathway have been established in the past 25 years (Figure 1). The proteasome degrades both immature and mature proteins to generate cytosolic peptides (1). The transporter associated with antigen processing (TAP) imports proteasome-generated cytosolic peptides into the endoplasmic reticulum (ER) where peptides assemble with MHC-I with the assistance of dedicated and general purpose molecular chaperones, followed by trafficking to the cell surface via the standard secretory pathway.
The effectiveness of MHC-I-based immunosurveillance is evident from the ubiquitous evolution of viral proteins that specifically interfere with antigen processing (1, 2). Similarly, many tumors impair antigen processing and peptide presentation to avoid immune eradication (3, 4), a process termed immunoevasion or immunoediting (5). How do tumors sabotage this system? We have likely only scratched the surface of this question, which is critical for distinguishing patients that are most likely to respond to immunotherapy and for devising treatments to convert resistant tumors. The standard approach has predominantly focused on sequencing tumor nucleic acids. This is no surprise, as a needle biopsy provides ample material for...