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Loss of LRRC33-Dependent TGFβ1 Activation Enhances Antitumor Immunity and Checkpoint Blockade Therapy
Aiping Jiang1,2, Yan Qin1,2, Timothy A Springer1,2
1Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.
Abstract:
TGFβ has multiple roles and gene products (TGFβ1, -β2, and -β3), which make global targeting of TGFβ undesirable. Expression of TGFβ requires association with milieu molecules, which localize TGFβ to the surface of specific cells or extracellular matrices. Here, we found that LRRC33 was specifically associated with TGFβ1, not TGFβ2 and TGFβ3, and was required for surface display and activation of TGFβ1 on tumor-infiltrating myeloid cells. Loss of LRRC33-dependent TGFβ1 activation slowed tumor growth and metastasis by enhancing innate and adaptive antitumor immunity in multiple mouse syngeneic tumor models. LRRC33 loss resulted in a more immunogenic microenvironment, with decreased myeloid-derived suppressor cells, more active CD8+ T and NK cells, and more skewing toward tumor-suppressive M1 macrophages. LRRC33 loss and PD-1 blockade synergized in controlling B16.F10 tumor growth. Our results demonstrate the importance of LRRC33 in tumor biology and highlight the therapeutic potential of dual blockade of the LRRC33/TGFβ1 axis and PD-1/PD-L1 in cancer immunotherapy.
Insights
Researchers identified LRRC33 as crucial for activating TGFβ1 on tumor cells. Blocking LRRC33 enhances anti-tumor immunity and slows cancer growth, showing potential for new immunotherapies.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Transforming growth factor-beta (TGFβ) has diverse roles, making broad targeting challenging.
- TGFβ requires association with other molecules for cell surface or extracellular matrix localization.
- Specific targeting strategies are needed to harness TGFβ's therapeutic potential while minimizing side effects.
Purpose of the Study:
- To investigate the role of LRRC33 in the display and activation of TGFβ1 on tumor-infiltrating myeloid cells.
- To evaluate the impact of inhibiting LRRC33-dependent TGFβ1 activation on tumor growth and metastasis.
- To explore the potential of targeting the LRRC33/TGFβ1 axis in cancer immunotherapy.
Main Methods:
- Utilized mouse syngeneic tumor models to assess tumor growth and metastasis.
- Analyzed the tumor microenvironment, including immune cell populations (myeloid-derived suppressor cells, CD8+ T cells, NK cells, M1 macrophages).
- Investigated the synergistic effects of LRRC33 inhibition and PD-1 blockade on tumor control.
Main Results:
- LRRC33 specifically associates with TGFβ1, mediating its surface display and activation on tumor-infiltrating myeloid cells.
- Loss of LRRC33-dependent TGFβ1 activation significantly slowed tumor growth and metastasis.
- LRRC33 inhibition promoted a more immunogenic tumor microenvironment, characterized by reduced myeloid-derived suppressor cells and enhanced CD8+ T and NK cell activity.
- LRRC33 loss and PD-1 blockade demonstrated synergistic effects in controlling tumor growth.
Conclusions:
- LRRC33 plays a critical role in TGFβ1-mediated tumor immune evasion.
- Targeting the LRRC33/TGFβ1 axis represents a promising strategy to enhance antitumor immunity.
- Dual blockade of the LRRC33/TGFβ1 axis and PD-1/PD-L1 axis holds significant therapeutic potential in cancer immunotherapy.
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