IRE1α Inhibition Enhances Chemo-Immunotherapy Response in Immunologically Cold Tumors
核心洞察
Researchers have discovered that the endoplasmic reticulum (ER) stress sensor IRE1α (搜索) limits the immunostimulatory activity of taxanes (搜索), a common class of chemotherapy drugs.
Inhibiting the RNase activity of IRE1α (搜索) can transform immunologically 'cold' tumors into 'hot' tumors, making them more responsive to chemo-immunotherapy.
In mouse models of triple-negative breast cancer (TNBC (搜索)), combining an IRE1α (搜索) RNase inhibitor (ORIN1001) with docetaxel led to increased T cell infiltration and PD-L1 upregulation.
Combining chemotherapy with immune checkpoint inhibitors (ICIs) has shown promise in enhancing immunotherapy outcomes, but many patients with immunologically 'cold' tumors do not respond effectively. Now, research indicates that the endoplasmic reticulum (ER) stress sensor IRE1α (搜索) limits the immunostimulatory activity of taxanes (搜索), a widely used class of chemotherapy drugs. Inhibiting the RNase activity of IRE1α can convert ICI-unresponsive tumors into immunologically 'hot' tumors, which are highly sensitive to chemo-immunotherapy. This suggests a novel approach to improve treatment efficacy in patients with tumors that are typically resistant to immunotherapy.
IRE1α Inhibition Promotes T Cell Infiltration
In three immunologically cold mouse models of triple-negative breast cancer (TNBC (搜索)), docetaxel chemotherapy reduced tumor volumes but did not significantly increase tumor-infiltrating lymphocyte (TIL) infiltrates. Treatment with ORIN1001, a selective IRE1α (搜索) RNase inhibitor, alone had no discernible effect on the tumors. However, the combination of ORIN1001 with docetaxel resulted in a substantial infiltration of TILs into the tumor microenvironment (TME). This suggests that inhibiting IRE1α can enhance the immune response within the tumor.
Sensitization to PD-1 Inhibitors
Importantly, the combination therapy, but not the single-agent therapies, converted the TNBC (搜索) tumors from PD-L1 negative to PD-L1 high. This upregulation of PD-L1 sensitized the tumors to PD-1 inhibitors (搜索). This finding is clinically significant because PD-L1 expression is often associated with better responses to immune checkpoint inhibitors. The study highlights the potential of targeting IRE1α (搜索) to overcome resistance mechanisms in immunologically cold tumors and improve the efficacy of chemo-immunotherapy regimens.