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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer
Aditi Gupta1,2, Sadna Budhu1,2, Kelly Fitzgerald1,2
1Swim Across America and Ludwig Collaborative Laboratory, Immunology Program, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Abstract:
TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression.
Insights
Transforming growth factor beta (TGFβ) inhibition in stroma-poor tumors enhances CD8+ T cell function, improving tumor control. Combining TGFβ inhibition with immune checkpoint blockade further boosts anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Transforming growth factor beta (TGFβ) plays a complex role in cancer, acting as both a tumor promoter and suppressor.
- Previous research on TGFβ inhibition in cancer has primarily focused on tumors with abundant stromal components.
- The role and therapeutic potential of TGFβ inhibition in stroma-poor tumors remain less understood.
Purpose of the Study:
- To investigate the sources and roles of TGFβ isoforms in stroma-poor tumor models (B16 melanoma, CT26 colon carcinoma).
- To evaluate the efficacy of isoform-specific TGFβ inhibition in controlling tumor growth.
- To explore the combination of TGFβ inhibition with immune checkpoint blockade for enhanced anti-tumor effects.
Main Methods:
- Utilized B16 mouse melanoma and CT26 colon carcinoma as stroma-poor tumor models.
- Identified TGFβ-producing cells within the tumor microenvironment.
- Administered isoform-specific TGFβ inhibitors (anti-TGFβ1 or anti-TGFβ3) and assessed tumor growth.
- Performed T cell functional assays to elucidate the mechanism of tumor suppression.
- Combined TGFβ inhibition with immune checkpoint blockade and evaluated tumor control.
Main Results:
- Myeloid/dendritic cells were identified as the primary sources of TGFβ1 and TGFβ3 in stroma-poor tumors.
- Inhibition of TGFβ1 in CT26 tumors and either TGFβ1 or TGFβ3 in B16 tumors resulted in tumor growth delay.
- Tumor suppression was mediated by enhanced CD8+ T cell function.
- Combination therapy of TGFβ inhibition and immune checkpoint blockade significantly improved tumor control.
Conclusions:
- TGFβ inhibition is a viable strategy for stroma-poor tumors, with isoform-specific approaches showing promise.
- The anti-tumor effect of TGFβ inhibition is dependent on enhancing CD8+ T cell-mediated immunity.
- Combining TGFβ inhibition with immune checkpoint blockade represents a potent strategy to overcome local immunosuppression and improve cancer treatment outcomes.
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