Major histocompatibility class I (MHC I) molecules bind peptides derived from a cell's expressed genes and then transport and display this antigenic information on the cell surface. This allows CD8 T cells to identify pathological cells that are synthesizing abnormal proteins, such as cancers that are expressing mutated proteins. In order for many cancers to arise and progress, they need to evolve mechanisms to avoid elimination by CD8 T cells. MHC I molecules are not essential for cell survival and therefore one mechanism by which cancers can evade immune control is by losing MHC I antigen presentation machinery (APM). Not only will this impair the ability of natural immune responses to control cancers, but also frustrate immunotherapies that work by re-invigorating anti-tumor CD8 T cells, such as checkpoint blockade. Here we review the evidence that loss of MHC I antigen presentation is a frequent occurrence in many cancers. We discuss new insights into some common underlying mechanisms through which some cancers inactivate the MHC I pathway and consider some possible strategies to overcome this limitation in ways that could restore immune control of tumors and improve immunotherapy.

/pdf/cancer-immune-evasion-through-loss-of-mhc-class-i-antigen-25ts7p6mf1.pdf

Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation.

Preclinical characterization of 1-7F9, a novel human anti–KIR receptor therapeutic antibody that augments natural killer–mediated killing of tumor cells

Inflammatory cell infiltration of tumors contributes either positively or negatively to tumor invasion, growth, metastasis, and patient outcomes, creating a Dr. Jekyll or Mr. Hyde conundrum when examining mechanisms of action. This is due to tumor heterogeneity and the diversity of the inflammatory cell phenotypes that infiltrate primary and metastatic lesions. Tumor infiltration by macrophages is generally associated with neoangiogenesis and negative outcomes, whereas dendritic cell (DC) infiltration is typically associated with a positive clinical outcome in association with their ability to present tumor antigens (Ags) and induce Ag-specific T cell responses. Myeloid-derived suppressor cells (MDSCs) also infiltrate tumors, inhibiting immune responses and facilitating tumor growth and metastasis. In contrast, T cell infiltration of tumors provides a positive prognostic surrogate, although subset analyses suggest that not all infiltrating T cells predict a positive outcome. In general, infiltration by CD8+ T cells predicts a positive outcome, while CD4+ cells predict a negative outcome. Therefore, the analysis of cellular phenotypes and potentially spatial distribution of infiltrating cells are critical for an accurate assessment of outcome. Similarly, cellular infiltration of metastatic foci is also a critical parameter for inducing therapeutic responses, as well as establishing tumor dormancy. Current strategies for cellular, gene, and molecular therapies are focused on the manipulation of infiltrating cellular populations. Within this review, we discuss the role of tumor infiltrating, myeloid-monocytic cells, and T lymphocytes, as well as their potential for tumor control, immunosuppression, and facilitation of metastasis.

Inflammatory cell infiltration of tumors : Jekyll or Hyde

Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis

In colorectal cancer, the immune response is particularly pronounced against tumors displaying the high microsatellite instability (MSI-H) phenotype. MSI-H tumors accumulate mutations affecting microsatellites located within protein encoding regions (coding microsatellites, cMS), which lead to translational shifts of the respective reading frames. Consequently, novel tumor-specific frameshift-derived neopeptides (FSP) are generated and presented by MSI-H tumor cells, thus eliciting effective cytotoxic immune responses. To analyze whether the immunoselective pressure was reflected by the phenotype of MSI-H colorectal cancer cells, we compared here the expression of antigen processing machinery (APM) components and human leukocyte antigen (HLA) class I antigen subunits in 20 MSI-H and 20 microsatellite-stable (MSS) colorectal cancer using a panel of newly developed APM component-specific monoclonal antibodies. In addition, we did a systematic analysis of mutations at cMS located within APM genes and beta2-microglobulin (beta2m). Total HLA class I antigen loss was observed in 12 (60.0%) of the 20 MSI-H lesions compared with only 6 (30.0%) of the 20 MSS colorectal cancer lesions. Moreover, total loss of membraneous HLA-A staining was significantly more frequent in MSI-H colorectal cancer (P = 0.0024). Mutations at cMS of beta2m and genes encoding APM components (TAP1 and TAP2) were detected in at least 7 (35.0%) of 20 MSI-H colorectal cancers but in none of the MSS colorectal cancers (P = 0.0002). These data show that defects of HLA class I antigen processing and presentation seem to be significantly more frequent in MSI-H than in MSS colorectal cancer, suggesting that in MSI-H colorectal cancer the immunoselective pressure leads to the outgrowth of cells with defects of antigen presentation.

https://cancerres.aacrjournals.org/content/canres/65/14/6418.full.pdf

Immunoselective Pressure and Human Leukocyte Antigen Class I Antigen Machinery Defects in Microsatellite Unstable Colorectal Cancers

Down-regulation of HLA-A expression correlates with a better prognosis in colorectal cancer patients.

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Down-regulation of HLA-A expression correlates with a better prognosis in colorectal cancer patients.