Tumours often avoid detection by CD8+ T cells through disrupting peptide presentation by major histocompatibility complex class I (MHC-I). However, how this is accomplished is not well understood. A recent study, published in Cell, used genome-wide screens in human diffuse large B cell lymphomas (DLBCLs). Their screens revealed dozens of genes which regulate MHC-I surface expression.
CD8+ T cells circulate the human body, on the lookout for malignant or pathogen infected cells. They recognise these aberrant cells via antigens, which are presented on the cell surface by the major histocompatibility complex I (MHC-I). However, this presentation can be downregulated by malignant cells, but the mechanisms of this process are poorly understood.
Diffuse large B cell lymphoma (DLBCL) is a form of cancer which commonly relapses following chemotherapy treatment. Around 40-75% of DLBCL biopsies show abnormal MHC-I expression or localisation within cells. Therefore, it is likely that immune evasion is a key mechanism underlying cases of relapse. To understand the role of antigen presentation more fully in cancer, this study explored the regulation of the MHC complexes in DLBCL. They used genome wide CRISPR-Cas9 screening to investigate the genes involved in antigen presentation.
Results of Genome-Wide Screens
Genome-wide screens revealed dozens of genes which had not previously been linked to antigen processing and presentation. The findings of this study demonstrate that genetic alterations in antigen processing and presentation machinery is common in DLBCL. Using an unbiased screening process, they found that regulators of MHC-I in one tumour type are likely to play similar roles in other cancers, expanding the repertoire of known immune evasion factors.
These screens also identified many genes which are known to co-regulate MHC-I and MHC-II. The MHC-II complex is involved in a separate form of antitumor immunosurveillance. B cells express the MHC-II complex on their cell surface, and this is recognised by CD4+ T cells. These CD4+ T cells also exhibit anti-tumour activity: they can directly lyse tumour cells or enhance tumour lysis by other immune cells. This data suggests that genes can simultaneously co-regulate both complexes which can have major implications for T-cell recognition of tumours.
Generally, immunotherapies have focused on the manipulation of T cells, rather than the promotion of tumour peptide presentation. However, T-cell targeted therapies are unlikely to work for tumours which evade immune detection. Therefore, the researchers conducted a small molecule screen to identify targets which may enhance surface MHC-I antigen presentation instead.
Their data suggested that inhibitors of both EZH2 (a component of the PCR2 transcription complex) and thymidylate synthase (TS) may enhance the effectiveness of immunotherapy for DLBCL. This could be achieved both by direct cytotoxicity and the enhancement of immunogenicity of tumour cells. Importantly, tumours resistant to one treatment could benefit from other MHC-I augmenting drugs.
Although this study specifically focused on B cell lymphomas, it is likely that some of the MHC-I regulators identified will be active in other tumour types and in healthy tissues. The involvement of these genes in other forms of cancer should be explored.