IOR: promising breakthrough in prostate cancer therapy

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Institutional Communication Service

21 July 2023

The Molecular Oncology research group, led by Prof. Andrea Alimonti at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+), has discovered that prostate cancer cells hijacked the translation machinery to recruit immunosuppressive myeloid cells that aid in evading the immune system. The study, conducted by Daniela Brina, revealed that the blockade of the translation machinery inhibits the recruitment of immunosuppressive myeloid cells and improves the efficacy of conventional immunotherapy. 

The study is published in Nature cancer: https://www.nature.com/articles/s43018-023-00594-z

 

Background

Myeloid-derived suppressor cells (MDSCs) are immune cells that suppress tumor anti-immune responses and promote tumor growth.

In prostate cancer, MDSCs count correlates with tumor aggressiveness and is associated with a poor prognosis in many tumors.

The main receptor on the surface of MDSCs, CXCR2, allows them to be recruited into tumors. Nonetheless, in mouse models of prostate cancer, the inhibition of CXCR2 does not completely abrogate MDSCs recruitment into the tumor.

Inhibiting CXCR2 has shown promising results in clinical trials, but some patients still do not respond to this therapy.

 

The discovery

Daniela Brina and colleagues conducted a study to identify proteins involved in the interaction between prostate cancer cells and MDSCs.

Interestingly, the proteins that prostate cancer cells produce with higher efficiency (higher number of proteins produced per mRNA) were largely involved in immune cell recruitment.

This suggests that influencing immune cell recruitment into tumors is a 'priority' for tumor cells.

Bgn-Tlr2, Spp1-Cd44, and Hgf-Met were the most highly expressed among the ligand-receptor pairs identified. These proteins were found to promote the migration of MDSCs and enhance their ability to suppress T cells. Deleting these genes in prostate cancer mouse models decreased MDSC recruitment and tumor growth.

Notably, these three MDSCs recruiters are highly expressed in advanced prostate cancer and correlated with the CD33 myeloid marker.

The most striking alterations observed in the factors involved in translation regulation are the phosphorylation of eIF4e and the downregulation of the tumor suppressor PDCD4, both in mouse and human prostate cancer. These alterations lead to a hyperactivation of the eIF4F initiation complex that allows to efficiently translate proteins otherwise produced at lower levels.

Thus, the study revealed that the translation machinery may be a therapeutic vulnerability of prostate cancer cells.

To block eIF4e phosphorylation and rescue PDCD4 levels, the researchers tested two translation inhibitors, eFT508 and ipatasertib, respectively, in two models of prostate cancer.

Inhibiting translation reduced tumor growth and MDSC recruitment and increased the anti-tumor immune responses in a Pten null;Trp53 null mouse model of aggressive prostate cancer. Moreover, in the Pten null;TMPRSS2/ERG genetic context, characterized by high expression of Cxcr2 ligands, the efficacy of the aCxcr2 inhibitor was potentiated by the treatment with the translation inhibitors, allowing to reach a more robust anti-tumor immune response compared to the single treatment.

 

Outlook

The findings of this study showed that targeting the translation machinery reduces the expression of recruiters of immunosuppressive myeloid cells into the tumor, providing the rationale for combining translation inhibitors with conventional immunotherapy to counteract immune evasion and unleash the immune system against cancer cells. The stratification of patients according to the NLR (neutrophil-to-lymphocyte ratio), PTEN, TP53 and TMPRSS2/ERG status will allow to identify patients potentially benefit from these treatments.

 

The study

“The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells” is the title of the study conducted at the IOR.To access the full version of the study, please refer to the publication in Nature Cancer  https://www.nature.com/articles/s43018-023-00594-z

 

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