Targeting eicosanoid metabolism to overcome tumor immunosuppression

Project Information

EicoMet

Grant agreement ID: 101123280

DOI

10.3030/101123280

Project closed

EC signature date 15 December 2023

Start date 1 February 2024

End date 31 July 2025

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

VIB VZW
Belgium

Periodic Reporting for period 1 - EicoMet (Targeting eicosanoid metabolism to overcome tumor immunosuppression)

Reporting period: 2024-02-01 to 2025-07-31

Summary of the context and overall objectives of the project

Although the field of cancer immunotherapy has seen exciting therapeutic advances over the past decade, a large number of patients with solid tumors display resistance. Melanoma is the most aggressive form of skin cancer and the first approved tumor indication for immune checkpoint blockade (ICB) therapies. Currently, αPD1 alone or in combination with αCTLA4 is the first-line treatment for metastatic melanoma. However, 65% of patients with melanoma still do not respond to ICB. According to the International Agency for Research on Cancer, the annual number of melanoma cases is predicted to increase by more than 50% by 2040. Therefore, additional strategies to induce antitumor immunity, alone or in combination with available immunotherapeutic drugs, are urgently needed. Specifically, our work demonstrated that T-cell activation influences the tumor microenvironment (TME) by reducing the release of prostaglandin D2 (PGD2) in tumor-associated macrophages (TAMs). Congruently, genetic or pharmacological inhibition of the enzyme responsible for PGD2 release, namely hematopoietic prostaglandin D2 synthase (HPGDS), induces anti-tumoral features in TAMs, favoring CD8+ T cell recruitment, activation, and cytotoxicity, altogether sensitizing the tumor to αPD1. With the contribution of this grant, we investigated the involvement of the two PGD2 receptors, DP1 and DP2 in the observed phenotype, and we expanded the relevance of HPGDS-DP1-DP2 inhibition in hepatocellular carcinoma (HCC).

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the frame of this PoC grant, we confirmed our preliminary results; investigated the relevance of the two PD2 receptors, DP1 and DP2 in melanoma; and extended our findings in HCC.
Particularly, part of the obtained results (only melanoma and PDAC) resulted in 1 high-impact scientific publication (Trotta et al., Cancer Discovery 2025), one manuscript under preparation related to the HCC model and three patents (EP23210278.0; EP23210284.8; EP23210290.5).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

In the frame of this PoC grant, we achieved all set objectives.

Thanks to the deep investigation (i) of the mechanism behind the sensitization to anti-PD1 mediated by HPGDS inhibition and (ii) of the anti-tumoral role of DP1 and DP2 inhibition, we obtained a high-impact scientific publication (Trotta et al., Cancer Discovery, 2022). In addition, thanks to the work sponsored by this ERC PoC, we were able to expand the field of application from melanoma to include HCC.