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Immature Cells Enhance Chemotherapy in Pancreatic Cancer

A new study published in Nature has found that during chemotherapy, immature immune cells called megakaryocyte-erythroid progenitors (MEPs) enhance the immune system’s response to cancer cells in a mouse model of pancreatic cancer.

Pancreatic cancer has a high mortality rate and limited treatment options; the main treatment options include combinations of chemotherapy drugs such as nab-paclitaxel and gemcitabine. Chemotherapy works by causing DNA damage in cancer cells, which leads to their death. However, it can also enhance the immune system’s response to cancer cells, which can eventually result in long-lasting anti-tumour immunity via a process called immunomodulation.

What is immunomodulation?

When chemotherapy causes cancer cells to die, their death can activate the immune system. This is termed immunogenic cell death (ICD) – and is characterized by changes in the composition of the cell surface and the release of certain immune system mediators (such as Damage-Associated Molecular Patterns (DAMPs), which include ATP, calreticulin and High Mobility Group Box 1 HMGB1). These signals are recognized by special receptors on immune cells, which then stimulate the presentation of tumour antigens to T-cells, activating the immune system to attack and eliminate cancer cells. This activation and modulation of the immune system by chemotherapy treatment is termed immunomodulation – and is an important process that can significantly increase the efficacy of chemotherapy.

Whilst ICD and chemotherapy-induced immunomodulation have both been studied extensively, the role of immature immune cells in this process has not. Haematopoietic stem and progenitor cells (HSPCs) are a type of immature immune cells that differentiate into some of the immune cells which colonize tumours and have immunosuppressive properties in response to tumour stimuli. In this study, researchers used a mouse pancreatic cancer model to investigate the effects of gemcitabine, a type of chemotherapy drug, on HSPCs as well as the role of HSPCs in anti-tumour immunity.

The effect of chemotherapy

Single-cell RNA sequencing of HSPCs revealed a 3-fold increase in megakaryocyte-erythroid progenitors (MEPs) in the bone marrow of gemcitabine-treated mice in comparison to untreated control mice – MEPs differentiate into the cells that produce red blood cells and platelets. Adoptive transfer of MEPs to pancreatic tumour-bearing mice significantly reduced tumour growth and increased the levels of anti-tumour immune cells in tumours and peripheral blood. Furthermore, MEPs increased the tumour cell-killing activity of CD8 + T cells and NK cells, an effect that was dependent on MEP-secreted chemokines CCL5 and CXCL16.

Figure 1: Schematic of pathways associated with genes expressed by MEPs – assessed by GO and CXCL16 and CCL5 displayed as hubs

Altogether, these findings show for the first time that chemotherapy-induced enrichment of MEPs in the bone marrow compartment contributes to anti-tumour immunity in this mouse model of pancreatic cancer. This highlights an additional mechanism – immunomodulation – by which chemotherapy exerts a therapeutic effect. Moreover, this may explain the synergistic therapeutic effect seen when chemotherapy is combined with immunotherapy. If these findings translate to humans, we could look to increase the efficacy of chemotherapy drugs, or develop immunotherapies, which enhance or activate the action of HSPCs and MEPs.

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