Wang Likun's team discovered a new mechanism by which tumor cell unfolded proteins respond to regulate tumor immunity

The accumulation of misfolded proteins in the lumen of the endoplasmic reticulum causes ER stress (ERS), which activates unfolded protein responses (UPRs
).
。 UPR consists of three signaling pathways: IRE1 (inositol-requiring enzyme 1), PERK (PKR-like ER-resident kinase), and ATF6α (activating transcription factor 6α).

Studies in recent years have found that UPR is closely
related to the occurrence and development of a variety of diseases, including cancer, diabetes, neurodegenerative diseases, etc.
Cells in tumor tissues face harsh environments such as hypoxia, nutrient deprivation, acidity, and metabolic changes within tumor cells, impaired genome integrity, and peroxide accumulation, all of which can cause endoplasmic reticulum stress and cause UPR
.
Studies have shown that tumor cells help cells survive
by using UPR to relieve endoplasmic reticulum pressure.
On the other hand, the regulation of immune cells by UPR has also been reported
.
At present, the research on the relationship between UPR and cancer mainly focuses on the regulation of UPR signaling on the function of tumor cells or immune cells in the tumor microenvironment
.
However, the tumor microenvironment is extremely complex, consisting of a variety of cells and intercellular stroma, and it is still unclear
whether the UPR signal in tumor cells affects the function of surrounding immune cells by regulating its own secreted factors.

On November 8, 2022, Wang Likun's team from the Institute of Biophysics, Chinese Academy of Sciences presented a video presentation on Cell Metabolism The journal published a research paper
titled "Cancer cell-intrinsic XBP1 drives immunosuppressive reprogramming of intratumoral myeloid cells by promoting cholesterol production.
" 。 The study found that the activation of IRE1α/XBP1 signaling pathway in tumor cells inhibits anti-tumor immunity and promotes tumor growth
by promoting the synthesis and secretion of own cholesterol.

Using mouse models of melanoma and colon cancer, the research group found that knocking out tumor cells IRE1αα or XBP1 can effectively inhibit the growth of tumors in wild-type mice, but does not affect the growth of
tumors in immunodeficient mice.
This indicates that IRE1α/XBP1 signaling in tumor cells promotes tumor growth
by regulating tumor immunity.
The researchers further used mass spectrometry flow cytometry to find that the deletion of XBP1 in tumor cells reduced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and increased the activated CD8 T cells
.

In order to better understand the regulatory effect of XBP1 on tumor immunity in tumor cells, the researchers found through transcriptome sequencing and lipidomics analysis that the deletion of XBP1 in tumor cells reduced the level of
cholesterol in tumor tissues.
Using ChIP-PCR technology, the researchers found that XBP1 is a transcriptional
regulator of HMGCR, a key enzyme in the cholesterol synthesis pathway.
In vitro experiments have also found that cholesterol can stimulate the activation and expansion
of MDSCs.
At the same time, inhibition of cholesterol synthesis in tumor cells can significantly reduce the level of MDSC in tumors and increase the number of CD8 T cells, thereby limiting tumor growth
.
These results suggest that XBP1 in tumor cells negatively regulates anti-tumor immunity
by promoting cholesterol synthesis.

Next, the research group conducted an in-depth study
of how cholesterol is transmitted by tumor cells to MDSC and how MDSC receives cholesterol.
Since small extracellular vesicles (sEVs) are common mediators of cell-to-cell signaling, the researchers explored whether XBP1 regulates sEV secretion or changes
in cholesterol on sEVs.
They found that knocking down tumor cell XBP1 reduced the secretion of sEVs as well as cholesterol levels
on sEVs.
Moreover, the ability of XBP1-deficient tumor cell-derived sEVs to stimulate MDSC expansion and activation is greatly impaired
.
In addition, while stimulated with sEV, the inhibition of MDSC macropinocytosis also significantly limited the amplification and activation of MDSC
.
These studies have shown that cholesterol within tumor cells is transmitted to MDSC via sEV, and MDSC takes up cholesterol
through macropinocytosis.

Finally, the research group found that KIRA8, an inhibitor of IRE1α/XBP1 signaling pathway, can significantly inhibit tumor growth, and combined with PD-1 antibody has a better effect on tumor treatment
.

In summary, this study revealed the mechanism of IRE1α/XBP1 signaling pathway in tumor cells regulating tumor immunity, and found the new function of UPR to regulate cholesterol synthesis and participate in cross-cell signaling, which provides a new vision
for the development of new anti-tumor drugs.

Pattern diagram (quoted from original)

On the left, the UPR signaling molecule XBP1 of tumor cells upregulates HMGCR expression and cholesterol synthesis, which is secreted through sEV form and taken up by MDSC, promoting the amplification and activation of MDSC and inhibiting anti-tumor immunity
.
On the right, KIRA8, a kinase inhibitor of IRE1α, effectively restores CD8 T cell activity and restricts tumor growth
.

Dr.
Zaili Yang (graduated from Likun Wang's group, now a postdoctoral fellow at Tsinghua University) is the first author of the research paper, and researcher Wang Likun from the Institute of Biophysics is the corresponding author
of the paper.

Article link:

(Contributed by: Wang Likun Research Group)