CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma

Xiaofang Wu, The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, George Washington University, Washington, DC, United States.
Priya Srinivasan, The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, George Washington University, Washington, DC, United States.
Mousumi Basu, The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, George Washington University, Washington, DC, United States.
Talia Zimmerman, The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, George Washington University, Washington, DC, United States.
Samuel Li, The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, George Washington University, Washington, DC, United States.
Yin Wang, University of Maryland Medical Center, University of Maryland, Baltimore, MD, United States.
Pan Zheng, OncoC4. Inc, Rockville, MD, United States.
Yang Liu, OncoC4. Inc, Rockville, MD, United States.
Anthony David Sandler, The Joseph E. Robert Jr. Center for Surgical Care and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, George Washington University, Washington, DC, United States.

Document Type

Journal Article

Publication Date

1-1-2023

Journal

Frontiers in immunology

Volume

14

DOI

10.3389/fimmu.2023.1176370

Keywords

CD24Fc; autoimmune profiling; immune-related adverse events; neuroblastoma; tumor cell vaccine

Abstract

INTRODUCTION: The combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model. METHODS: To test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining. RESULTS: The whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart. DISCUSSION: This study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.

Department

Surgery

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