Blocking MICA/MICB Shedding Reactivates Antitumor Immunity

The stress-induced antigens MICA and MICB are ligands of the natural killer (NK) group 2 receptor (NKG2D), which is expressed on NK and CD8⁺ T cells, and expression of MICA and MICB is elevated during pathogenic infection and in many cancers. However, although pathogenic infections result in an NK-mediated immune response, tumor-related proteases induce the proteolytic shedding of tumor MICA and MICB and thus inhibit NK cell–mediated antitumor immunity. To prevent the proteolytic shedding of tumor MICA and MICB, Ferrari de Andrade and colleagues immunized mice with the MICA and MICB α3 domain, which is the target site of proteases. Anti-MICA/MICB α3 antibodies inhibited MICA shedding and increased cell-surface MICA expression in a panel of human cancer cell lines. The monoclonal antibody 7C6, which exhibited the greatest efficacy in MICA and MICB cell-surface stabilization, enhanced NK cell activity against human cancer cell lines in vitro, inhibited the metastatic ability of murine melanoma (B16/F10) and colon cancer (CT26) cell lines transduced with MICA in vivo in an NK cell–dependent manner, and inhibited the growth of subcutaneous B16/F10 tumors transduced with MICA or MICB. Single-cell RNA sequencing of group 1 innate lymphoid cells (ILC), which are comprised of NK cells and ILCs, isolated from MICA⁺ B16/F10 lung metastases post–7C6 therapy, revealed that 7C6 treatment activates tumor-infiltrating NK cells and upregulates a cytotoxic gene signature. Consistent with these findings, treatment with an anti-NKG2D antibody or transplantation of NKG2D⁻/CD16⁻ NK cells reduced 7C6-mediated inhibition of MICA⁺ B16/F10 lung metastases or subcutaneous tumors, respectively. 7C6 inhibited lung metastasis and increased survival in immunodeficient mice reconstituted with human NK cells and subsequently inoculated with a highly metastatic human melanoma cell line. These results show that targeting MICA and MICB shedding enhances NK cell–mediated antitumor immunity and suggest that anti-MICA/MICB antibodies are a potential immunotherapy for cancer.

Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity. Science 2018;359:1537–42.

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