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Background: Ewing sarcoma is a rare tumor of the bone or soft tissues characterized by diffuse membranous staining for CD99. As this tumor remains incurable in the metastatic, relapsed, and refractory settings, we explored the downstream immune implications of targeting CD99. Methods: We discovered a human anti-CD99 antibody (NOA2) by phagemid panning and investigated NOA2 immune cell-mediated cytotoxicity in vitro and in vivo focusing on the myeloid cell compartment, given that M2 macrophages are present in human tumors and associated with a poor prognosis. Results: NOA2 is capable of inducing immune effector cell-mediated Ewing death in vitro via engagement of macrophages. Mice with metastatic Ewing tumors, treated with NOA2, experience tumor growth arrest and an associated increase in intratumoral macrophages. Further, incubation of macrophages and Ewing cells with NOA2, in conjunction with anti-PILRα antibody blockade in vitro, results in the reactivation of previously dormant macrophages possibly due to interrupted binding of Ewing CD99 to macrophage PILRα. Conclusions: These studies are the first to demonstrate the role of human immune effector cells in anti-CD99-mediated Ewing tumor death. We propose that the engagement of CD99 by NOA2 results in the recruitment of intratumoral macrophages. In addition, interruption of the CD99:PILRα checkpoint axis may be a relevant therapeutic approach to activate tumor-associated macrophages. [ABSTRACT FROM AUTHOR]

Since the SARS-CoV-2 Omicron variant (B.1.1.529) was declared a variant of concern (VOC) by the WHO on 24 November 2021, it has caused another global surge of cases. With extensive mutations in its spike glycoprotein, Omicron gained substantial capabilities to evade the antiviral immunity provided by vaccination, hybrid immunity, or monoclonal antibodies. The Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4 and BA.5 extended this immune evasion capability by having additional unique mutations in their respective spike proteins. The ongoing Omicron wave and emergence of new Omicron subvariants leads to additional concerns regarding the efficacy of the current antiviral measurements. To have a better understanding of the Omicron subvariants, this review summarizes reports of the immune evasion of subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 as well as the molecular basis of immune evasion. [ABSTRACT FROM AUTHOR]