Targeting bicarbonate transport as a “first-in-class” therapeutic strategy to promote CD8+ T cell fitness and enhance cancer immunotherapy

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancer types. It is virtually resistant to any sort of therapy, including the most recent immunotherapies.

Tumor Microenvironment

These tumors are characterized by a strong hypoxic, nutrient-poor, and acidic tumor microenvironment (TME), in which cytotoxic CD8+ T cells are excluded or absent. In the context of tumor acidity, the role of bicarbonate transporters, key regulators of pH homeostasis, has mostly been neglected so far.

Research Findings

Supported by the ERC consolidator grant ImmunoFit, we recently unveiled that the metabolic editing of the TME via inhibition of a specific bicarbonate transporter in cancer cells represents a novel robust therapeutic strategy to:

1. Mitigate the acidity of the TME
2. Increase the fitness of CD8+ T cells
3. Render more effective the current immunotherapeutic regimens in pancreatic cancer

Proposed Strategy

To progress on the path from ground-breaking research towards innovation, we now propose to de-risk the target by delivering early lead compounds (i.e., blockers) with proven therapeutic efficacy and synergism with immunotherapies in several preclinical tumor models.

Collaboration and Commercialization

These compounds will be valorized for add-on cancer therapy through follow-up R&D collaborations and/or licensing agreements with Pharmaceutical & Biotech companies. This will lead to the commercialization of our sciences and broad societal impact with the deliverable of a brand-new therapeutic approach and combination regimens which are urgently required to tackle tumor resistance or refractoriness vis-à-vis immunotherapies.