Deciphering Antigen Processing Machinery (APM) as One of the Determinants for Responsiveness of Affected Patients...

Immunotherapy is one of the rising stars in the field of anticancer regiments. Aimed at reinvigorating immune cytotoxicity, this platform is capable of bulking up memory subsets by which protection against tumors is served. The most commonly applied immunotherapy is immune checkpoint inhibitor (ICIs) which received FDA approval for non-small lung cancer (NSLC) in 2014. The response toward ICI is closely related to the antigen processing machinery (APM) within which antigens are processed prior to loading onto the human leukocyte antigen (HLA) to induce cascade mechanisms for immune clearance. APM allows immune cell infiltration thus strengthens immunogenicity. Impaired components of the APM are frequently found in tumors because tumor progression requires tumor cells to acquire immune recognition evasion. Alterations in tumors' APM result in downregulation of HLA molecules and transformation of antigenic peptide repertoire presented to the T lymphocytes. Interactions of processed antigens (peptide)-HLA complex are critical for successful T cell priming and differentiation into cytotoxic effector cells. The interaction underlies not only ICI-related mechanism but also anticancer immunity in general where T cell subset can induce antitumor recognition only if a proper peptide-HLA complex is present. This feature, unfortunately, is missing in tumors. This Review highlights presentation of tumor-specific antigens to T cells in HLA-restricted manner which leads to their eradication. This is a pivotal point but in most cases is overlooked which might add some volume to the off-target and less functional of anticancer immunotherapy.