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

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.