Periodic Reporting for period 1 - EicoMet (Targeting eicosanoid metabolism to overcome tumor immunosuppression)
Período documentado: 2024-02-01 hasta 2025-07-31
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).
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).
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).
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.
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.