Abstract A84: B7-H3 promotes antitumor T-cell suppression via MDSCs in colorectal cancer

Abstract

Abstract One of the mechanisms causing resistance to checkpoint inhibitor treatment is accumulation of suppressive immune cells including myeloid-derived suppressor cells (MDSCs). In CRC patients, accumulation of MDSCs correlates with poor overall survival. Among a subset of CRC patients with high mutation burden, 31.1% respond to checkpoint inhibitor treatment. This implies that targeting resistance mechanisms such as MDSCs in these CRC patients could boost the efficacy of this treatment. B7-H3 (CD279), a member of the B7 family, is expressed on myeloid cells and suppresses T-cell proliferation. Therefore, we hypothesize that B7-H3 on MDSCs could promote CRC tumor growth by suppressing cytotoxic CD8 T cells. We used polyps from ApcMin/+ mice, an intestinal tumor model and a transplantable CRC tumor model such as MC38 colon carcinoma to assess the role of B7-H3. Our findings show that B7-H3 is upregulated in ApcMin/+ polyps and is expressed on in vitro derived monocytic MDSCs (M-MDSCs). The frequency of MDSCs increased with tumor growth, indicating the close correlation between MDSCs and disease burden. Blocking B7-H3 with an antibody in MC38 tumor model significantly reduced tumor volume (control group receiving isotype antibody: 1672.2 ± 121 mm3; B7-H3 antibody treated group: 892.7 ± 36.4 mm3; p<0.05). The frequency of CD4 and CD8 T cells in spleens and tumors of B7-H3 antibody-treated mice was increased, but this was not statistically significant. However, the frequency of CD8 cells producing IFNγ or granzyme B was significantly increased in tumors of B7-H3 antibody-treated mice. This shows that inhibition of B7-H3 in CRC regresses tumor growth and expands cytotoxic CD8 T cells in MC38 tumors. Previously we showed that reduction of intestinal tumors in ApcMin/+Stat6-/- mice correlated with reduced MDSCs and increased CD8 cytotoxic activity, indicating that MDSCs suppressed CD8 cells. Therefore, B7-H3 suppresses cytotoxic CD8 response in colon carcinoma, possibly by mediating the suppressive function of MDSCs. Clinical trials using dual targeting antibodies to B7-H3 and CD3 recruit T cells to kill tumor cells expressing B7-H3. However, impaired T-cell effector function by MDSCs could limit the efficacy of this therapy. Targeting B7-H3 on MDSCs could overcome resistance and boost the efficacy of combination treatments. Citation Format: Asha Jayakumar, Alfred Bothwell. B7-H3 promotes antitumor T-cell suppression via MDSCs in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A84.