Prolyl isomerase Pin1 sculpts the immune microenvironment of colorectal cancer

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Pin1 (peptide prolyl cis-trans isomerase) is implicated in human malignancies.
• The role of Pin1 in regulating the tumor microenvironment (TME) and its impact on immune cells and checkpoints remains unclear.
• Colorectal cancer (CRC) is a significant area of study for novel therapeutic targets.

Purpose of the Study:

• To investigate the effect of Pin1 on immune cells and PD-L1 expression within the CRC TME.
• To evaluate the anti-tumor efficacy of combining a Pin1 inhibitor (ATRA) with a PD-1 antibody.
• To elucidate the molecular mechanisms by which Pin1 influences PD-L1 stability and ER stress.

Main Methods:

• Analysis of immune cell populations (MDSCs, CD8+ T cells, CD4+ T cells) in the CRC TME.
• Assessment of PD-L1 protein expression in CRC cells under varying Pin1 activity and ER stress conditions.
• In vivo studies using a CRC allograft model to evaluate combination therapy with ATRA and PD-1 antibody.

Main Results:

• Pin1 overexpression was found to promote an immunosuppressive TME by increasing myeloid-derived suppressor cells (MDSCs) and decreasing CD8+ and CD4+ T cells.
• Pin1 negatively regulates PD-L1 protein expression by decreasing its stability and promoting degradation, partly through mitigating endoplasmic reticulum (ER) stress.
• Inhibition or silencing of Pin1 led to increased PD-L1 protein expression by inducing ER stress, thereby enhancing the anti-tumor efficacy of PD-1 antibody in CRC allografts.

Conclusions:

• Pin1 plays a critical role in modulating immune cell composition and PD-L1 expression within the CRC TME.
• Targeting Pin1 with inhibitors like ATRA can upregulate PD-L1, potentially sensitizing tumors to PD-1 blockade therapy.
• The combination of Pin1 inhibitors and PD-1 antibodies presents a promising therapeutic strategy for colorectal cancer immunotherapy.