Targeting eicosanoid metabolism to overcome tumor immunosuppression

Introduction

The field of cancer immunotherapy has witnessed exciting therapeutic advances in the last decade. However, a large fraction of patients remains unresponsive, and several cancer types are refractory to this therapy. The presence of a strongly immunosuppressive environment is a likely explanation for the suboptimal efficacy of immunotherapy.

Tumor-Associated Macrophages

One of the most abundant and immunosuppressive populations in the tumor microenvironment (TME) is represented by tumor-associated macrophages (TAMs). Therefore, several strategies that sculpt the TAM phenotype away from their immunosuppressive state are expected to become the next generation of immunotherapies.

Novel Therapeutic Strategy

Supported by the ERC consolidator grant ImmunoFit, we recently unveiled that the metabolic editing of the TME via the pharmacological and genetic inhibition of HPGDS in macrophages (an enzyme involved in the production of prostaglandin D2 from arachidonic acid) represents a novel therapeutic strategy. This strategy aims to:

1. Sculpt TAMs away from their immunosuppressive state.
2. Increase infiltration and fitness of CD8+ T cells and NK cells.
3. Promote tumor vessel normalization.

This change in the TME upon HPGDS inhibition overcomes resistance to current immunotherapeutic regimens in melanoma and other cancer indications.

Project Goals

This proposal aims to de-risk HPGDS targeting by delivering a lead compound with proven efficacy in several preclinical models. The deliverables of this project will open up a window of opportunities in immune-oncology and lead to novel combination therapies by increasing the potency of the current therapeutic approaches.