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TMP195 Exerts Antitumor Effects on Colorectal Cancer by Promoting M1 Macrophages Polarization
Yicheng Han1, Jiachun Sun2, Yanyan Yang1
1Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Abstract:
Studies have shown that epigenetic enzymes such as histone deacetylase (HDAC) are closely related to cancers and that several HDAC inhibitors exert antitumor effects. Studies have further suggested that class IIa HDAC inhibitors are related to immune functions, including immune responses and the expression of chemokines and complement pathway components. TMP195, a selective class IIa HDAC inhibitor, has been reported to be effective against breast cancer. However, the role and mechanism of TMP195 in colorectal cancer remain unknown. In this study, we found that TMP195 significantly reduced the tumor burden in two mouse models of colitis-associated colorectal cancer (CAC) and subcutaneous tumor. Mechanistically, TMP195 decreased the proportion of total macrophages but increased the proportion of M1 macrophages by promoting polarization, resulting in the increased release of inflammatory cytokines. TMP195 had no direct effect on the proliferation of colorectal cancer cells, and its antitumor effect on the colorectal cancer disappeared when macrophages were partly depleted by clodronate liposomes. In addition, TMP195 enhanced the efficacy of PD-1 blockade. The present study revealed that the combination of TMP195 and PD-1 blockade may provide a therapeutic strategy for colorectal cancer.
Insights
TMP195, a class IIa HDAC inhibitor, effectively reduces colorectal cancer tumor burden by promoting M1 macrophage polarization. This epigenetic therapy enhances PD-1 blockade efficacy, offering a new strategy for colorectal cancer treatment.
Area of Science:
- Oncology
- Immunology
- Epigenetics
Background:
- Histone deacetylase (HDAC) inhibitors are linked to cancer and immune functions.
- Class IIa HDAC inhibitors, like TMP195, show promise but their role in colorectal cancer is unclear.
- TMP195 has demonstrated efficacy in breast cancer models.
Purpose of the Study:
- To investigate the role and mechanism of TMP195 in colorectal cancer.
- To evaluate TMP195's antitumor effects and its impact on the tumor microenvironment.
- To assess TMP195's potential in combination with PD-1 blockade.
Main Methods:
- Utilized mouse models of colitis-associated colorectal cancer (CAC) and subcutaneous tumors.
- Administered TMP195, a selective class IIa HDAC inhibitor.
- Analyzed macrophage polarization (M1/M2) and cytokine release.
- Assessed TMP195's direct effect on cancer cell proliferation.
- Investigated the role of macrophages using clodronate liposomes.
- Evaluated the combination therapy with PD-1 blockade.
Main Results:
- TMP195 significantly reduced tumor burden in CAC and subcutaneous tumor models.
- TMP195 promoted M1 macrophage polarization, increasing inflammatory cytokine release.
- TMP195 did not directly affect colorectal cancer cell proliferation.
- Antitumor effects were dependent on the presence of macrophages.
- TMP195 enhanced the efficacy of PD-1 blockade therapy.
Conclusions:
- TMP195 exhibits antitumor effects in colorectal cancer, primarily through modulating macrophage polarization.
- The efficacy of TMP195 relies on its interaction with tumor-associated macrophages.
- Combining TMP195 with PD-1 blockade presents a promising therapeutic strategy for colorectal cancer.
