How p53 modulates the tumor immune microenvironment microbiologystudy

Although there are tumor suppressor genes in normal cells to prevent cancer, gene mutations can cause a normal cell to become a cancerous one. Among those genes, TP53 (encoding the p53 protein) has been identified as the most frequently mutated gene that causes cancer.

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

As a revolutionary therapy, immune checkpoint inhibitors (ICIs) have improved survival outcomes in the clinic. However, the majority of the patients turn out to experience ICI resistance, rather than a long-term and durable response. The efficacy of ICIs is determined by TIME, in which tumor-associated macrophages (TAMs) are the most abundant immune population with strong immunosuppressive ability. Currently, we have already known some mechanisms of how TAMs can inhibit the antitumor activity of T cells. Nevertheless, how p53 modulates TIME is still elusive.

Researchers found that the loss of p53 function led to the secretion of IL-34 directly. But the blockade of IL-34 restrained the growth of liver cancer with p53 inactivation, and thus prolonged the survival of mice in the experiment.

The researchers also discovered that p53 repressed IL34 transcription. Loss of p53 function brought about the release of IL-34 by cancer stem cells (CSCs), it also led to the accumulation of TAMs near the CSCs.

In addition, IL-34 exposure resulted in noteworthy increased CD36 expression, causing the TAMs to polarize toward the pro-tumoral phenotype. Finally, CD8⁺ T cell-mediated antitumor immunity to promote immune escape was suppressed.

Wondering whether blockade of the IL-34-CD36 axis could suppress tumor growth, researchers noticed that genetic deletion of IL34, together with anti-PD-1 treatment, synergized to curb tumor growth, with a complete response of up to 75%.

By comparison, tumors did not respond to anti-PD-1 treatment. The blockade of IL-34 signaling might serve as a potential immunotherapy for cancer patients with TP53 mutation.

The study casts new light on how to effectively treat cancer patients with TP53 mutations.