The role of neoantigens in response to immune checkpoint blockade

Abstract

Immune checkpoint blockade has demonstrated substantial promise for the treatment of several advanced malignancies. These agents activate the immune system to attack tumor cells. For example, agents targeting CTLA4 and programmed cell death 1 (PD-1) have resulted in impressive response rates and, in some cases, durable remissions. Neoantigens are mutations that encode immunologically active proteins that can cause the immune system to recognize the affected cell as foreign. Recent data have made it clear that these mutations are, in large part, the functional targets of immune checkpoint blockade. This review summarizes the key discoveries leading up to this important conclusion and discusses possible applications of neoantigens in cancer therapy.

T cell receptor repertoire profiling predicts the prognosis of HBV‐associated hepatocellular carcinoma

“…Theoretically, malignant tumor progression was associated with the increase of tumor mutation load and the generation of immunogenic neoantigens,26, 27 forming an extremely different local microenvironment in tumor tissue. T cell repertoire would correspondingly evolve with the change of neoantigens, and gradually deviate from the T cell repertoire in adjacent normal tissues.…”

Mismatch Repair Protein Deficiency Is a Risk Factor for Aberrant Expression of HLA Class I Molecules: A Putative "Adaptive Immune Escape" Phenomenon

“…This association is because frequent DNA mutation due to impairment of the MMR machinery would promote the occasional generation of highly antigenic neoantigens that are targeted by CTLs (8). However, tumors with high antigenicity often change their phenotype in response to cytotoxic and pro-inflammatory immune responses by overexpressing immune suppressive molecules such as PD-L1 (14).…”

“…Patients with an MMR protein deficiency can be identified using immunohistochemistry (IHC) for MutL protein homolog 1 (MLH1), MutS protein homolog 2 (MSH2), MutS protein homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2) or polymerase chain reaction for microsatellite instability (6). Currently, patients with colorectal adenocarcinoma with loss of these MMR proteins are suggested to be promising candidates for the application of targeted immune checkpoint inhibition therapy, presumably because deficiencies in these proteins lead to frequent generation of neo-antigens, which can have high antigenicity (7,8). The crucial event of cancer immunotherapy is the recognition by the T-cell receptor on CD8-positive CTLs of the antigen presented on the human leukocyte antigen (HLA) class I complex of tumor cells (9).…”

Radiation Recall Masquerading as an Infectious Process

“…Radiation produces neoantigens in the tissues [16], and PD-1 inhibitors' enhancement of the immune system to attack the tumor antigens could theoretically lead to an increase in inflammation of tissues exposed to radiation. More laboratory and clinical studies are needed to understand the role of neoantigens in the inflammatory cascade and radiation recall [17].…”