How Do Cancer Cells Successfully Avoid Natural Killer and Tc Cells Through Actin Responses?
Understanding how cancer cells evade immune system recognition, particularly by natural killer (NK) cells and cytotoxic T lymphocytes (Tc cells), is crucial for developing effective cancer therapies. While much is known about how cancer cells can avoid immune detection through various mechanisms, a noteworthy strategy involves the actin response. Here, we explore the underlying mechanisms of this fascinating and efficient defense mechanism used by some cancer cells.
A Quick Introduction to NK and Tc Cells
Natural killer cells are a type of cytolytic lymphocyte responsible for identifying and destroying cells that are infected or displaying signs of being cancerous. They recognize missing or altered Major Histocompatibility Complex (MHC) I molecules, which are typically present on healthy cells, as a sign that the cell is potentially dangerous. Once recognized, they dock to the cancer cell and induce apoptosis or lysis through the release of cytotoxic enzymes.
The Role of the Cytoskeleton and Actin Respones
In cancer research, a particularly intriguing mechanism involves the rearrangement of the actin cytoskeleton, focusing on the specific accumulation of filamentous actin (F-actin) near the site of contact between the NK cell and the cancer cell. This phenomenon, referred to as the actin response, has been observed in breast cancer but is likely a larger mechanism employed by various cancers to evade immune detection.
Characterization of the Actin Response
Researchers utilized live cell imaging to study the interaction between NK cells and breast cancer cells. The images revealed that only in cancer cells where an NK cell docked would an actin response occur, characterized by the accumulation of F-actin around the immunological synapse (IS) region. This response was noted to be stronger in some cells than in others, and more intense actin responses were associated with higher survival rates post-NK cell attack.
Cell Line Analysis and Subpopulations
Studying two cell lines, epithelial (susceptible to NK cells) and mesenchymal (resistant), further elucidated how the actin response plays a role. Interestingly, the researchers found that within these cell lines, there were subpopulations with varying levels of actin response. This led to the conclusion that the actin response itself was the key defense mechanism, as cells with stronger actin responses were better able to resist NK cell attack.
Knockout Experiment and Actin Function
To confirm the role of F-actin, the researchers performed a knockout experiment, removing proteins necessary for F-actin formation. Strikingly, without F-actin, all cells became equally vulnerable to NK cell attack, confirming that the actin response is indeed crucial for evasion.
Receptor Interference and Enzyme Blockage
Further experimentation revealed that the actin response interfered with NK cell docking and prevented the release of cytotoxic enzymes like granzyme B, which are crucial for inducing cell apoptosis. This interference likely slows down the NK cell's ability to efficiently act on the cancer cells, providing a critical survival advantage.
Cellular State and EMT/MET
The researchers also investigated the effect of the epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) on the actin response. Forced transitions showed that the state of a cell being either epithelial or mesenchymal directly influenced its resistance to NK cell attack. Given that excessive EMT is associated with several types of breast cancer, this finding provides a potential explanation for how these cancers can evade immune surveillance and take hold.
Summary
In conclusion, the actin response is a critical mechanism through which some cancer cells, particularly those undergoing EMT, can evade NK cell-mediated cytotoxicity. By accumulating F-actin at the site of NK cell contact, cancer cells can interfere with the NK cell's ability to dock and release cytotoxic enzymes, thereby avoiding cell death. The study of these responses not only adds to our basic understanding of cancer biology but also opens up new avenues for developing targeted immunotherapies to combat these cunning defenses.
Keywords: actin response, cancer cell escape, NK cell cytotoxicity, natural killer cells, Tc cells