Abstract 4492: Humanized anti-EGFR antibody panitumumab inhibits tumor growth of inflammatory breast cancer by inducing antitumor immunity
Authors: Xiaoping Wang, Shan Shao, Takashi Semba, Troy Pearson, James M. Re, Debu Tripathy, Naoto Ueno
Journal: Cancer Research (2019)

Abstract Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer, yet no approved targeted therapies specifically for IBC have been approved. The epidermal growth factor receptor (EGFR) pathway is a promising therapeutic target for patients with triple-negative IBC, with a reported pathological complete response rate of 42%. The tumor microenvironment (TME) is a critical contributor to the aggressiveness of IBC. Therefore, delineating the cross-talk between EGFR-targeted therapy and TME components could lead to more efficient combination regimens and novel clinical trial designs for IBC. Because an immunocompetent IBC animal model is not available for our study, we established an IBC SUM149 immunocompetent mouse model (SUM149-hu-NSG-SGM3) for such studies. Here we report the effects of panitumumab (PmAb), a humanized monoclonal anti-EGFR antibody, on tumor growth and on the TME in the SUM149-hu-NSG-SMG3 mouse model. Methods: SUM149 cells were mixed with 50% Matrigel and inoculated into mammary fat pads of hu-NSG-SGM3 mice engrafted with human hematopoietic stem cells. SUM149 tumor growth in mice treated with either isotype IgG2 or PmAb was measured. We used flow cytometry to measure the percentages of human immune cells in the peripheral blood and tumor tissues from mice treated with IgG2 and PmAb. The effects of PmAb treatment on the expression and distribution of TME components in tumor tissues was examined by multiplex immunohistochemical staining. Cytokine expression in tumor tissues from IgG2- and PmAb-treated mice was measured by cytokine antibody array, and the changes in cytokines expression were validated with RT-PCR. Results: PmAb treatment, compared with IgG2 treatment, significantly reduced SUM149 tumor growth. Flow cytometry analysis showed infiltration of lymphocytes in SUM149 tumors with an observed increase in the level of CD8+ T cells and a reduced level of Tregs in both peripheral blood and tumor tissues from PmAb-treated mice compared with IgG2-treated mice. Cytokine array and RT-PCR showed that PmAb treatment increased expression of cytokines that function as a chemoattractant for T cells, natural killer cells, and monocytes, including CXCL10, CCL5, CCL4, and CXCL9. In contrast, PmAb treatment reduced expression of cytokines involved in antitumor immune suppression, including osteoprotegerin (OPG), CCL2, CXCL5, and CCL20. Conclusion: PmAb treatment reduced IBC tumor growth by increasing cytotoxic T cells and reducing immunosuppressive Treg cells. Our data also suggest that the combination of PmAb with an immune checkpoint inhibitor may potentiate the efficacy of anti-EGFR therapy in IBC. A study of the therapeutic efficacy of the PmAb and anti-PD-L1 combination in the SUM149-hu-NSG-SMG3 mouse model is in progress. Citation Format: Xiaoping Wang, Shan Shao, Takashi Semba, Troy Pearson, James M. Re, Debu Tripathy, Naoto Ueno. Humanized anti-EGFR antibody panitumumab inhibits tumor growth of inflammatory breast cancer by inducing antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4492.