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June 8, 2018

Tumor Biology Study Suggests Promising New Route to Cancer Drug Development

View of cells within a mouse tumor with increasing magnification. Tumor-associated macrophages show red fluorescence and antitumor T cells show magenta fluorescence. [Dr. Fabien Garcon/Babraham Institute]

  • Scientists at the Babraham Institute say they have shown that some tumors use not one but two levels of protection against the immune system. Knocking out one level boosted the protective effects of the second and vice versa. The research demonstrates that a two-pronged approach targeting both cell types simultaneously may offer a promising route for the development of new cancer immunotherapies, according to the researchers.

    The study (“Compensation between CSF1R+ Macrophages and Foxp3+ Treg Cells Drives Resistance to Tumor Immunotherapy”) appears in JCI Insight.

    “Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 [colony-stimulating factor 1] in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs,” write the investigators.”

    “Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kδ [phosphatidylinositol-3-kinase subunit delta], or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.”

    The development and growth of a cancerous tumor often occurs despite a fully functioning immune system, capable of recognizing and killing cancer cells. Tumors hijack certain cells in our immune system to create a growth-permissive environment and give protection from the antitumor elements. In particular, tumors recruit immune cell allies, cells called TAMs and Treg cells, to evade immune attack. 

    Specifically inhibiting the recruitment of TAMs by blocking the actions of the CSF1 protein reduces tumor growth in mouse models. Although clinical trials of inhibitors targeting TAMs are underway, results in patients haven't been as effective as hoped. A lack of understanding of how TAMs promote tumor progression potentially limits the therapeutic value of these inhibitors.

    Likewise, inhibiting the action of Treg cells in mice by inactivating a key enzyme called PI3Kδ gives protection against a range of tumors. A PI3Kδ inhibitor is approved for treatment of chronic lymphocytic leukemia (CLL) and follicular non-Hodgkin lymphoma (NHL), but the potential for PI3Kδ inhibitors for the treatment of solid cancers in humans is yet to be demonstrated. 

    The research described in the current journal article used a mouse model of colorectal cancer to explore the synergy between TAMs and Treg cells, showing that each cell type was able to compensate for the effects of the loss of the other to maintain the tumor's protection from the immune system. However, jointly inhibiting TAMs and Treg cells substantially inhibited tumor growth. 

    "Strikingly, preventing tumor immunosuppression by both TAMs and Treg cells caused almost complete tumor rejection by the immune system and half of the mice became completely tumor-free. Taken together, our findings provide a convincing rationale for assessing the clinical value of combinatorial therapies targeting the CSF1 receptor and PI3Kδ,” said David Gyori, Ph.D., first author on the paper.

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