Abstract P1-04-06: Semaphorin7a expression in breast cancers promotes susceptibility to immune checkpoint blockade
Authors: Alan Elder, Alexander Stoller, Traci Lyons
Journal: Cancer Research (2022)

Abstract Five-year survival rates for women diagnosed with stage II breast cancer are &amp;gt;85% on average; however, in women diagnosed with stage II breast cancer (BC) within 10 years of last childbirth, we observe a 5-fold increase in risk for developing distant metastasis when compared with nulliparous women1. Major driving factors for stage II diagnosis include increased tumor-associated lymphatic vessel density (LVD), lymphovascular invasion (LVI), and lymph node positivity (LN+) and are all associated with poor prognosis for breast cancer patients. Nonetheless, the mechanisms underlying development of LN metastasis, and how LN metastasis seed distant metastases, has remained elusive. LVD, LVI, and LN+ can be driven by tumor-associated macrophages (TAMs), which have been implicated in creating a pro-tumor tumor microenvironment (TME) in many types of cancer. Additionally, podoplanin (PDPN)-expressing macrophages (PoEMs), are a newly characterized type of TAM that specifically contribute to tumor-associated lymphatic vessel formation2,3. Our lab identified that semaphorin7A (SEMA7A)—a neuroimmune molecule—is significantly associated with increased metastasis in LN+, but not LN-, BC patients, as well as increased recurrence in cases of BCs diagnosed within 10 years of childbirth, designated postpartum breast cancers (PPBCs). In mouse models, SEMA7A expression is associated with increased LVD and TAM presence, including PoEMs3. Furthermore, we and others have shown that PoEMs intercalate into lymphatic vessels to form PoEM-LEC chimeric vessels, where tumor cells can often be found at the PoEM-LEC junctions2. We have also observed that breast cancer cells, lymphatics, macrophages, and PoEMs exhibit SEMA7A-dependent expression of PD-L1 in vitro, which may make SEMA7A+ tumors more sensitive to anti-PD-1/PD-L1 immunotherapies. Therefore, we utilized multiple orthotopic, immunocompetent mouse models to reveal that growth of SEMA7A overexpressing (OE) tumors, but not controls, was significantly slowed with both anti-PD-1 and anti-PD-L1 treatments. Flow cytometric analysis of cells from the TME revealed increased LECs, TAMs, and PoEMs in SEMA7A+ tumors, compared to controls—all populations had higher PD-L1 expression, which was decreased with both anti-PD-1 or anti-PD-L1. We also observed a decrease in PD-L1 expression on the tumor cells with treatment. Furthermore, LEC, TAM, and PoEM presence was decreased within the TME alongside increased presence of activated CD4 and CD8 T cells. Collectively, our results suggest that SEMA7A expression in breast cancers activates a major pathway associated with immune evasion and helps to establish a protumor microenvironment, which can be targeted with readily available FDA approved drugs such as immune checkpoint-based therapies. Since SEMA7A+ and PPBCs have high rates of metastasis, more specific treatments for these patient populations should be explored. 1.Goddard, E.T., et al. Association Between Postpartum Breast Cancer Diagnosis and Metastasis and the Clinical Features Underlying Risk. JAMA Netw Open 2, e186997 (2019). 2.Bieniasz-Krzywiec, P., et al. Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer. Cell Metab (2019). 3.Elder, A.M., et al. Semaphorin 7A Promotes Macrophage-Mediated Lymphatic Remodeling during Postpartum Mammary Gland Involution and in Breast Cancer. Cancer research 78, 6473-6485 (2018). Citation Format: Alan Elder, Alexander Stoller, Traci Lyons. Semaphorin7a expression in breast cancers promotes susceptibility to immune checkpoint blockade [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-04-06.