# The Role of the Ecto-Nucleotidases CD73 and CD39 in Chemo- and Immunotherapy

## TL;DR

This paper reviews how CD73 and CD39 proteins affect cancer immunotherapy and chemotherapy effectiveness, and how blocking them may improve treatment outcomes.

## Contribution

The paper highlights the novel role of CD73 and CD39 in modulating immunotherapy and chemotherapy responses and the potential of their inhibitors in cancer treatment.

## Key findings

- CD73 and CD39 produce adenosine, which suppresses immune responses and may reduce cancer therapy efficacy.
- Chemotherapy can increase CD73 and CD39 levels, potentially contributing to treatment resistance.
- Inhibitors of CD73 and CD39 show early promise in clinical trials for improving cancer treatment outcomes.

## Abstract

Immunotherapy has become an important treatment option for cancers with many genetic changes, such as melanoma and non-small cell lung cancer, and is often combined with chemotherapy. While these treatments can be effective, not all patients respond equally well. This review focuses on two proteins, CD73 and CD39, that are found on cancer cells and surrounding cells in the tumor environment. These proteins produce adenosine, a substance that weakens the immune response against tumors and may reduce the efficacy of cancer therapies. Chemotherapy can further increase the levels of these proteins, potentially contributing to treatment resistance. New drugs that block CD73 and CD39 are currently being tested and show promising early results. Understanding how these proteins influence combined cancer treatments may help improve future therapies and lead to better outcomes for patients.

Immunotherapy, particularly effective in tumors with a high mutational burden, is very often administered in combination with chemotherapy. Several tumor types with a high mutational rate include melanoma and non-small cell lung cancer (NSCLC), which are particularly sensitive to immunotherapy. For NSCLC, conventional platinum-based doublet chemotherapy has been extended with drugs targeting signaling pathways (such as the epidermal growth factor receptor) and immune checkpoint inhibitors (ICI) directed against PD-1 and PD-L1. This review highlights the potential role of the membrane antigens CD73 and CD39 in enhancing the efficacy of combined immuno-chemotherapy. These ecto-nucleotidases catalyze the degradation of extracellular ATP to AMP and subsequently to adenosine (Ado), a potent immunosuppressive metabolite that acts through adenosine receptors. Consequently, CD73 and CD39 function as key downregulators of immunogenic signaling. Both CD73 and CD39 are highly expressed not only on tumor cells but also on immune and endothelial cells within the tumor microenvironment. Conventional chemotherapy may further upregulate their expression, contributing to drug resistance and impaired immune responses. To counteract these effects, inhibitors of CD73 and CD39, both monoclonal antibodies and small molecules, are currently under clinical evaluation, with early results indicating potential therapeutic benefit. Although this evidence supports the involvement of CD73 and CD39 in modulating responses to immunotherapy, particularly in combination with chemotherapy, the precise mechanisms underlying these interactions remain unclear. Elucidating these pathways will be critical for optimizing treatment strategies and improving clinical outcomes in malignancies such as NSCLC. This review highlights the critical role of these pathways in optimizing treatment strategies and improving clinical outcomes in malignancies such as NSCLC.