Loss of LRRC33-Dependent TGFß1 Activation Enhances Antitumor Immunity and Checkpoint Blockade Therapy.

ABSTRACT

TGFß has multiple roles and gene products (TGFß1, -ß2, and -ß3), which make global targeting of TGFß undesirable. Expression of TGFß requires association with milieu molecules, which localize TGFß to the surface of specific cells or extracellular matrices. Here, we found that LRRC33 was specifically associated with TGFß1, not TGFß2 and TGFß3, and was required for surface display and activation of TGFß1 on tumor-infiltrating myeloid cells. Loss of LRRC33-dependent TGFß1 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/TGFß1 axis and PD-1/PD-L1 in cancer immunotherapy.