The Neo-Open Reading Frame Peptides That Comprise the Tumor Framome Are a Rich Source of Neoantigens for Cancer Immunotherapy.

Identification of immunogenic cancer neoantigens as targets for therapy is challenging. Here, we integrate the whole-genome and long-read transcript sequencing of cancers to identify the collection of neo-open reading frame peptides (NOP) expressed in tumors. We termed this collection of NOPs the tumor framome. NOPs represent tumor-specific peptides that are different from wild-type proteins and may be strongly immunogenic. We describe a class of hidden NOPs that derive from structural genomic variants involving an upstream protein coding gene driving expression and translation of noncoding regions of the genome downstream of a rearrangement breakpoint, i.e., where no gene annotation or evidence for transcription exists. The entire collection of NOPs represents a vast number of possible neoantigens particularly in tumors with many structural genomic variants and a low number of missense mutations. We show that NOPs are immunogenic and epitopes derived from NOPs can bind to MHC class I molecules. Finally, we provide evidence for the presence of memory T cells specific for hidden NOPs in peripheral blood from a patient with lung cancer. This work highlights NOPs as a major source of possible neoantigens for personalized cancer immunotherapy and provides a rationale for analyzing the complete cancer genome and transcriptome as a basis for the detection of NOPs.

Activated leukocyte cell adhesion molecule (ALCAM/CD166): signaling at the divide of melanoma cell clustering and cell migration?

Orchestrated modulation of cell adhesion is essential for development and homeostasis in multicellular organisms. It optimizes embedding of the cell in its dynamic environment and facilitates appropriate cell responses and intercellular communication. Chronic disturbance of this delicate equilibrium causes defects in tissue architecture and sometimes cancer. In tumor cell biology, dynamic control of adhesion molecules is important to proceed through the metastatic cascade and to allow cell release from the primary tumor, invasion of the surrounding matrix, intravasation and adhesion to vascular endothelial cells to facilitate extravasation. Intertwined and multiple adhesive interactions rather than individual interactions presumably play critical roles in neoplastic development. Yet, knowledge of the contribution of each individual adhesion molecule is essential to unravel this network of interactions. This review will focus on activated leukocyte cell adhesion molecule (ALCAM/CD166) and its role in human melanoma progression. It is hypothesized that ALCAM may function as a cell surface sensor to register local growth saturation and to regulate cellular signaling and dynamic responses.