Cancer has been jeopardizing the well-being of humankind. There are tumor suppressor genes in our normal cells to prevent, while the mutation of genes can lead a normal cell to become a cancerous one. Among those genes, TP53 (encoding the p53 protein) has been identified as the most frequently mutated one that cause human cancers.

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 was published on 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.

The graphical abstract of p53 mutation leading to immune escape. (Image by WEI et al.)

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, thus prolonged the the survival time of mice.

In further explorations, the researchers 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.

Besides, IL-34 exposure resulted in noteworthy increased CD36 expression, causing the TAMs polarizing toward 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, researchers noticed that genetic deletion of Il34, together with anti-PD-1 treatment, synergized to curb tumor growth, with a complete response in 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.

Paper link: https://doi.org/10.1016/j.immuni.2024.08.015

(Written by ZHENG Zihong, edited by HUANG Rui, USTC News Center)