HLA-mediated tumor escape mechanisms that may impair immunotherapy clinical outcomes via T-cell activation

Abstract

Although the immune system provides protection from cancer by means of immunosurveillance, which serves a major function in eliminating cancer cells, it may also lead to cancer immunoediting, molding tumor immunogenicity. Cancer cells exploit several molecular mechanisms to thwart immune-mediated death by disabling cellular components of the immune system associated with tumor recognition and rejection. Human leukocyte antigen (HLA) molecules are mandatory for the immune recognition and subsequent killing of neoplastic cells by the immune system, as tumor antigens must be presented in an HLA-restricted manner to be recognized by T-cell receptors. Impaired HLA-I expression prevents the activation of cytotoxic immune mechanisms, whereas impaired HLA-II expression affects the antigen-presenting capability of antigen presenting cells. Aberrant HLA-G expression by cancer cells favors immune escape by inhibiting the activities of virtually all immune cells. The development of cancer therapies based on T-cell activation must consider these HLA-associated immune evasion mechanisms, as alterations in their expression occur early and frequently in the majority of types of cancer, and have an adverse impact on the clinical response to immunotherapy. Herein, the concept of altered HLA expression as a mechanism exploited by tumors to escape immune control and induce an immunosuppressive environment is reviewed. A number of novel clinical immunotherapeutic approaches used for cancer treatment are also reviewed, and strategies for overcoming the limitations of these immunotherapeutic interventions are proposed.

Classification models for Invasive Ductal Carcinoma Progression, based on gene expression data-trained supervised machine learning

“…Gene features from the complete Gene expression-based models are more enriched in biological process related to immunological response such as T cell costimulation, immunoglobin response (Figure 9b). Impaired expression of HLA-DQB1 due to change in methylation pattern of gene is associated with esophageal squamous cell carcinoma by altering immune response pattern [49].…”

“Metastatic Cancer of Unknown Primary” or “Primary Metastatic Cancer”?

“…Reliable markers need yet to be established to predict responsiveness to immunotherapy and to identify the subset of patients expected to benefit the most. The most promising markers currently under study comprise microsatellite instability (MSI), high tumor mutational load (TML) (83,84), mismatch repair deficiency (dMMR) (85), HLA class-I diversity (86,87), and biomarker expression (e.g., PD1, PD-L1) (88). Screening 389 cases of CUP, Gatalica et al found that 28% of samples were positive for one or more of said predictive markers (89).…”

Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

“…Different TAAs expressed by CSCs, such as ALDH1A1, CD133, CEP55, COA-1, EpCam, HEATR1 IL-13Rα2, SOX2, and DNAJB8, are recognized by T cells and are potentially capable of eliciting an effective antitumor immune response [28]. To prevent attack by immune cells, neoplastic cells in clinically detectable tumors often downregulate the expression of proteins involved in ag presentation, thus preventing the exposure of TAAs in tumor cell membranes [29]. This phenomenon appears to be enhanced in CSCs of several cancer types.…”