Good news! Cancer is history one step at a time!
"Tumors can use an enzyme called ART1 to thwart antitumor immune cells, making the enzyme a promising new target for immunity-boosting cancer treatments ...
the researchers found strong evidence that ART1, when expressed on tumor cells, can modify a receptor on tumor-fighting immune cells in a way that triggers the death of these immune cells. In animal models of cancer, blocking ART1 increased the presence of the tumor-fighting immune cells within tumors and slowed or stopped tumor growth. ...
“Our main focus in this study was lung cancer, but there is evidence that this immune-evasion mechanism is at work also in other kinds of cancer,” ...
the researchers found strong evidence that ART1, when expressed on tumor cells, can modify a receptor on tumor-fighting immune cells in a way that triggers the death of these immune cells. In animal models of cancer, blocking ART1 increased the presence of the tumor-fighting immune cells within tumors and slowed or stopped tumor growth. ...
“Our main focus in this study was lung cancer, but there is evidence that this immune-evasion mechanism is at work also in other kinds of cancer,” ...
We then developed a therapeutic antibody that blocks the function of ART1, allows the immune system to fight the cancer and ultimately prolongs survival in tumor models. ...
The mammalian immune system has various safety mechanisms to prevent immune activity from becoming excessive and damaging tissues. Scientists in recent decades have come to appreciate that tumors frequently co-opt these safety mechanisms – also called immune checkpoints – to defeat natural antitumor immune responses. ...That appreciation has led, in turn, to the development of “immune checkpoint inhibitor” treatments that block these safety mechanisms to enhance antitumor immunity. These treatments are now part of standard care in several types of cancer and help account for some astounding cures. However, a large proportion of individual cancers do not respond to such therapies, which hints that these cancers may make use of other, so-far-unrevealed immune checkpoint systems.
ART1 appears to be part of one such immune-checkpoint exploitation system. ...""Most patients with non–small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)–induced cell death (NICD) of P2X7 receptor (P2X7R)–expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono–adenosine 5′-diphosphate (ADP)–ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R+ CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R+ CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD+-degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell–dependent manner. This was associated with increased infiltration of activated P2X7R+CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies."
Presumably, this is the underlying research article:
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