Loss of LRRC33-dependent TGFβ1 activation enhances anti-tumor immunity and checkpoint blockade therapy

TGF-β has multiple roles and gene products (TGF-β1, -β2, and -β3), which make global targeting of TGF-β undesirable. Expression of TGF-β requires association with milieu molecules, which localize TGF-β to the surface of specific cells or extracellular matrices. Here, we found that LRRC33 was specifically associated with TGF-β1, not -β2 and -β3, and was required for surface display and activation of TGF-β1 on tumor-infiltrating myeloid cells. Loss of LRRC33-dependent TGF-β1 activation slowed tumor growth and metastasis by enhancing innate and adaptive anti-tumor 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/TGF-β1 axis and PD-1/PD-L1 in cancer immunotherapy.