Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing

Abstract

Recent advances in lung cancer treatment are emerging from new immunotherapies that target T-cell inhibitory receptors, such as programmed cell death-1 (PD-1). However, responses to anti-PD-1 antibodies as single agents are observed in fewer than 20% of non-small-cell lung cancer (NSCLC) patients, and immune mechanisms involved in the response to these therapeutic interventions remain poorly elucidated. Accumulating evidence indicates that effective anti-tumor immunity is associated with the presence of T cells directed toward cancer neoepitopes, a class of major histocompatibility complex (MHC)-bound peptides that arise from tumor-specific mutations. Nevertheless, tumors frequently use multiple pathways to escape T-cell recognition and destruction. In this regard, primary and acquired resistance to immune checkpoint blockade (ICB) therapy was associated with alterations in genes relevant to antigen presentation by MHC-class I/beta-2-microglobulin (MHC-I/β2m) complexes to CD8 T lymphocytes. Among additional known mechanisms involved in tumor resistance to CD8 T-cell immunity, alterations in transporter associated with antigen processing (TAP) play a major role by inducing a sharp decrease in surface expression of MHC-I/β2m-peptide complexes, enabling malignant cells to evade cytotoxic T lymphocyte (CTL)-mediated killing. Therefore, development of novel immunotherapies based on tumor neoantigens, that are selectively presented by cancer cells carrying defects in antigen processing and presentation, and that are capable of inducing destruction of such transformed cells, is a major challenge in translational research for application in treatment of lung cancer. In this context, we previously identified a non-mutant tumor neoepitope, ppCT_16-25, derived from the preprocalcitonin (ppCT) leader sequence and processed independently of proteasomes/TAP by a mechanism involving signal peptidase (SP) and signal peptide peptidase (SPP). We also provided in vitro and in vivo proof of the concept of active immunotherapy based on ppCT-derived peptides capable of controlling growth of immune-escaped tumors expressing low levels of MHC-I molecules. Thus, non-mutant and mutant neoepitopes are promising T-cell targets for therapeutic cancer vaccines in combination with ICB. In this review, we summarize current treatments for lung cancer and discuss the promises that conserved neoantigens offer for more effective immunotherapies targeting immune-escaped tumor variants.

Keywords: T-cell epitope associated with impaired peptide processing; antigen presentation and processing; cancer immunotherapy; cancer vaccine; lung cancer; tumor escape.

Figure 1

Processing of CD8 ppCT T-cell epitopes. The ppCT signal peptide has a type II orientation (the NH2-terminal region exposed toward the cytosol and the COOH-terminal region facing the endoplasmic reticulum lumen). The ppCT₁₆₋₂₅ epitope is processed by SP and SPP independently of TAP, and is released directly into the endoplasmic reticulum (left). After cleavage by SP and SPP, a ppCT₁₋₁₇ signal peptide fragment is released into the cytoplasm, to be processed by the proteasome/TAP pathway so as to give rise to the ppCT₉₋₁₇ epitope. The ppCT₉₋₁₇ epitope may also be generated from a ppCT₁₋₁₇ signal peptide fragment by cytosolic proteases before transport into the endoplasmic reticulum lumen by TAP (middle). ppCT₅₀₋₅₉ and ppCT₉₁₋₁₀₀ epitopes are generated by the TAP/proteasome pathway after retrotranslocation of the pCT precursor protein from the endoplasmic reticulum lumen into the cytosol by the ERAD pathway (right). All generated ppCT epitopes bind within the endoplasmic reticulum to HLA-A2 molecules before externalization to the target cell membrane for recognition and elimination by specific CD8 T lymphocytes. ER, endoplasmic reticulum; MHC-I, MHC-class I; Ub, ubiquitin.