Targeting eicosanoid metabolism to overcome tumor immunosuppression

Informazioni relative al progetto

EicoMet

ID dell’accordo di sovvenzione: 101123280

DOI

10.3030/101123280

Progetto chiuso

Data della firma CE 15 Dicembre 2023

Data di avvio 1 Febbraio 2024

Data di completamento 31 Luglio 2025

Finanziato da

• European Research Council (ERC)

Costo totale

Nessun dato

Contributo UE

€ 150 000,00

Coordinato da

VIB VZW
Belgium

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

Periodo di rendicontazione: 2024-02-01 al 2025-07-31

Sintesi del contesto e degli obiettivi generali del progetto

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).

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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).

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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.