HMN 2025: How p53 modulates the tumor immune microenvironment

Although there are tumor suppressor genes in regular cells to stop cancer, gene mutations may cause a traditional cell to change into a cancerous one. Among these genes, TP53 (encoding the p53 protein) has been recognized as probably the most often mutated gene that causes cancer.

A analysis crew led by Prof. Wei Haiming from the University of Science and Technology of China (USTC) revealed the position of p53 in modulating the tumor immune microenvironment (TIME). The study is published in Immunity.

As a revolutionary remedy, immune checkpoint inhibitors (ICIs) have improved survival outcomes within the clinic. However, nearly all of the sufferers prove to expertise ICI resistance, reasonably than a long-term and sturdy response. The efficacy of ICIs is decided by TIME, through which tumor-associated macrophages (TAMs) are probably the most plentiful immune inhabitants with sturdy immunosuppressive capacity. Currently, we now have already recognized some mechanisms of how TAMs can inhibit the antitumor exercise of T cells. Nevertheless, how p53 modulates TIME continues to be elusive.

Researchers discovered that the lack of p53 perform led to the secretion of IL-34 immediately. But the blockade of IL-34 restrained the expansion of liver cancer with p53 inactivation, and thus extended the survival of mice within the experiment.

The researchers additionally found that p53 repressed IL34 transcription. Loss of p53 perform introduced in regards to the launch of IL-34 by cancer stem cells (CSCs), it additionally led to the buildup of TAMs close to the CSCs.

In addition, IL-34 publicity resulted in noteworthy elevated CD36 expression, inflicting the TAMs to polarize towards the pro-tumoral phenotype. Finally, CD8⁺ T cell-mediated antitumor immunity to advertise immune escape was suppressed.

Wondering whether or not blockade of the IL-34-CD36 axis may suppress tumor development, researchers observed that genetic deletion of IL34, along with anti-PD-1 remedy, synergized to curb tumor development, with an entire response of as much as 75%.

By comparability, tumors didn’t reply to anti-PD-1 remedy. The blockade of IL-34 signaling may function a possible immunotherapy for cancer sufferers with TP53 mutation.

The study casts new gentle on successfully deal with cancer sufferers with TP53 mutations.