Recent advances in
cancer treatment have emerged from new
immunotherapies targeting T-cell inhibitory receptors, including cytotoxic T-lymphocyte associated
antigen (CTLA)-4 and programmed cell death (PD)-1. In this context, anti-CTLA-4 and anti-PD-1
monoclonal antibodies have demonstrated survival benefits in numerous
cancers, including
melanoma and
non-small-cell lung carcinoma. PD-1-expressing CD8+ T lymphocytes appear to play a major role in the response to these
immune checkpoint inhibitors (ICI). Cytotoxic T lymphocytes (CTL) eliminate malignant cells through recognition by the
T-cell receptor (TCR) of specific antigenic
peptides presented on the surface of
cancer cells by major histocompatibility complex class I/
beta-2-microglobulin complexes, and through killing of target cells, mainly by releasing the content of secretory lysosomes containing
perforin and
granzyme B. T-cell adhesion molecules and, in particular,
lymphocyte-function-associated antigen-1 and CD103
integrins, and their cognate
ligands, respectively,
intercellular adhesion molecule 1 and
E-cadherin, on target cells, are involved in strengthening the interaction between CTL and
tumor cells.
Tumor-specific CTL have been isolated from tumor-infiltrating lymphocytes and peripheral blood lymphocytes (PBL) of patients with varied
cancers. TCRβ-chain gene usage indicated that CTL identified in vitro selectively expanded in vivo at the
tumor site compared to autologous PBL. Moreover, functional studies indicated that these CTL mediate
human leukocyte antigen class I-restricted cytotoxic activity toward autologous
tumor cells. Several of them recognize truly
tumor-specific
antigens encoded by mutated genes, also known as neoantigens, which likely play a key role in antitumor CD8 T-cell immunity. Accordingly, it has been shown that the presence of T lymphocytes directed toward
tumor neoantigens is associated with patient response to
immunotherapies, including ICI, adoptive cell transfer, and dendritic cell-based
vaccines. These
tumor-specific mutation-derived
antigens open up new perspectives for development of effective second-generation therapeutic
cancer vaccines.