Getting Cancer to Unmask Itself to be targeted by immune response

Amazing stuff! Cancer is history (soon)!

"... cancer cells often evade detection by displaying very few suspicious proteins that the immune system can identify and target. A new approach to cancer treatment ... increases the number of the immune system’s targets by disrupting protein production in cancerous cells. In a new study ... the researchers show that this disruption forces the cancer cells to expose themselves by producing dozens of suspicious proteins, which leads to a powerful immune response that is capable of destroying human cancer cells and slowing the development of aggressive tumors in mouse models. ...

However, many types of cancer harbor few mutations, leaving the immune system with very few effective targets for identifying and eradicating the cancer cells. ...

To disrupt the translation process in human melanoma cells, the research team ... used genetic engineering to delete one of those enzymes. The deletion caused the ribosome to misread the genetic instructions, incorrectly divide the words and produce proteins with the wrong amino acids. In their study the researchers identified 34 short proteins, uniquely synthesized in cancer cells, that had been disrupted, and showed that some of them could be effective new targets for triggering an immune response against the cancer. ..."

From the highlights and abstract:

"Highlights

• TYW2 loss induces ribosomal FS and immunogenic aberrant peptide MHC presentation

• Impaired translation fidelity limits tumor growth in a CD8+ T cell-dependent manner

• Tyw2 KO enhances CD8+ T cell infiltration into tumors and sensitivity to ICB

• TYW2 expression predicts survival and ICB response in patients with primary melanoma

Summary

Aberrant peptides presented by major histocompatibility complex (MHC) molecules are targets for tumor eradication, as these peptides can be recognized as foreign by T cells.

Protein synthesis in malignant cells is dysregulated, which may result in the generation and presentation of aberrant peptides that can be exploited for T cell-based therapies.

To investigate the role of translational dysregulation in immunological tumor control, we disrupt translation fidelity by deleting tRNA wybutosine (yW)-synthesizing protein 2 (TYW2) in tumor cells and characterize the downstream impact on translation fidelity and immunogenicity using immunopeptidomics, genomics, and functional assays. These analyses reveal that TYW2 knockout (KO) cells generate immunogenic out-of-frame peptides.

Furthermore, Tyw2 loss increases tumor immunogenicity and leads to anti-programmed cell death 1 (PD-1) checkpoint blockade sensitivity in vivo. Importantly, reduced TYW2 expression is associated with increased response to checkpoint blockade in patients.

Together, we demonstrate that defects in translation fidelity drive tumor immunogenicity and may be leveraged for cancer immunotherapy."

Getting Cancer to Unmask Itself - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries "Researchers ... manipulated cancer cells into making themselves visible to the immune system, creating a new approach that gives hope to patients with previously untreatable disease"

Translation dysregulation in cancer as a source for targetable antigens (open access)

Graphical abstract

After the translation process in tumor cells was disrupted (left), many more killer T cells (red) penetrated the tumor environment, as compared to the same growth in which the translation process was intact (right). Other types of immune cells are in blue