Mesenchymal stem cells elicits Anti-PD1 immunotherapy by targeted delivery of CX3CL1
Jize Liu1,2, Xiaomin Ma1, Chuxuan Liu3
1Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, China.
Abstract:
Anti-PD1/PDL1 monotherapy has failed to acquire sufficiently ideal results in most solid tumors. Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on some tumors, but the functions of MSCs in colorectal cancer (CRC) need further research. In this study, we aimed to investigate the therapeutic effect and the improvement of sensitivity of MSCs to anti-PD1 antibodies (αPD1) in CRC and to evaluate the possible mechanism. The relative distribution of immune cells in tumor microenvironment was examined after the mice were treated with MSC and/or αPD1. Our study revealed that MSC recruits CX3CR1high macrophages and promotes M1 polarization to inhibit tumor growth via highly secretion of CX3CL1.The combination of MSC and αPD1 was superior to monotherapy against CRC. MSC inhibits PD1 expression on CD8+ T cells by facilitating M1 macrophage polarization, which promotes the proliferation of CD8+ T cells, thus improving the sensitivity to αPD1 therapy in CRC. Additionally, the above therapeutic effect disappeared after inhibiting the secretion of CX3CL1 in MSC. Our MSC-based immunotherapeutic strategy simultaneously recruited and activated immune effector cells at the tumor site, suggesting that the combination of MSC and αPD1 could be a potential therapy for CRC.
Insights
Mesenchymal stem cells (MSCs) enhance anti-PD1 therapy for colorectal cancer (CRC) by reprogramming the tumor microenvironment. This combination therapy boosts immune cell activity, offering a promising new treatment strategy for CRC.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Anti-PD1/PDL1 immunotherapy shows limited efficacy in many solid tumors, including colorectal cancer (CRC).
- Mesenchymal stem cells (MSCs) have demonstrated anti-tumor potential, but their role in CRC and synergy with immunotherapy requires further investigation.
Purpose of the Study:
- To investigate the therapeutic potential of MSCs in CRC.
- To evaluate if MSCs can enhance the sensitivity of CRC to anti-PD1 antibodies (αPD1).
- To elucidate the underlying mechanisms of MSC-mediated immune modulation in CRC.
Main Methods:
- Mice with colorectal cancer were treated with MSCs and/or αPD1.
- Immune cell distribution within the tumor microenvironment was analyzed.
- CX3CL1 secretion and M1 macrophage polarization were assessed.
Main Results:
- MSCs recruited CX3CR1high macrophages and promoted M1 polarization via CX3CL1 secretion, inhibiting tumor growth.
- Combination therapy (MSC + αPD1) was more effective than monotherapy.
- MSCs reduced PD1 expression on CD8+ T cells by enhancing M1 macrophage polarization, leading to increased CD8+ T cell proliferation and improved αPD1 sensitivity.
- Inhibiting MSC-derived CX3CL1 abolished the therapeutic effects.
Conclusions:
- MSCs enhance anti-PD1 therapy for colorectal cancer by modulating the tumor microenvironment.
- The combination of MSCs and αPD1 represents a potential immunotherapeutic strategy for CRC by recruiting and activating immune effector cells.
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