Antagonizing Integrin β3 Increases Immunosuppression in Cancer

Abstract

Integrin beta3 is critical for tumor invasion, neoangiogenesis, and inflammation making it a promising cancer target. However, preclinical and clinical data of integrin beta3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin beta3 could affect tumor immunity and evaluated tumors in mice integrin beta3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin beta3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T-cells. Integrin beta3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells wherein integrin beta3 signaling favored STAT1 activation, an M1 polarizing signal, and suppressed M2 polarizing STAT6 activation. Finally, disruption of CD8+ T-cells, macrophages, or macrophage integrin beta3 signaling blocked the tumor-promoting effects of integrin beta3 antagonism. These results suggest that effects of integrin beta3 therapies on immune cells should be considered to improve outcomes.

Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

“…The murine C57BL/6 PyMT-Bo1 luminal B breast cancer cell line (stably expressing GFP and firefly luciferase genes) was originally isolated from a transgenic MMTV-PyMT breast tumor, as previously validated and described (20). The murine BALB/c 4T1 triple-negative breast cancer cell line was purchased from ATCC, as previously described (31).…”

“…In vivo and ex vivo BLI was performed on IVIS50 (PerkinElmer, Waltham, MA) as previously described (20). Total photon flux (photons/sec) was measured from fixed regions of interest (ROIs) over entire mouse or manually around ex vivo organs using Living Image 2.6, as indicated.…”

“…Specifically, integrin αvβ3 is composed of the tightly regulated integrin subunit β3 and the more widely expressed αv subunit. Expression of αvβ3 on most cells in the body is typically low, but is elevated on several cancer types (17), as well as a variety of cell types that are important within the tumor microenvironment, such as osteoclasts (11,12), neo-angiogenic endothelium (19), and tumor-promoting macrophages (20). The expression of αvβ3 on these cells led to the investigation of αvβ3 as a therapeutic target for cancer treatment (21).…”

“…In several clinical trials, pharmacological inhibition with αvβ3 antagonists as a single-agent cancer therapy did not demonstrate a significant clinical effect (22,23). We, and others, have demonstrated that the inefficiency of αvβ3 inhibitors in advanced cancer may be due to the inherent complexities of integrin signaling and off-target effects of αvβ3 antagonism (20,24). …”

Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

“…16 This failure was explained by the observation that low doses of Cilengitide actually stimulate VEGF-induced angiogenesis instead of producing the expected antiangiogenic activity, 17 and that Cilengitide can enhance tumor growth by augmenting the activity of tumorpromoting M2 macrophages. 18 RGD-based peptides have been more successful as targeted imaging probes, 19 as shown in melanoma patients. 20 At the preclinical level, they also serve as a drug delivery system.…”