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Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

ABSTRACT: The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2⁺ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

SUBMITTER: Theruvath J

PROVIDER: S-EPMC9098186 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

Theruvath Johanna J Menard Marie M Smith Benjamin A H BAH Linde Miles H MH Coles Garry L GL Dalton Guillermo Nicolas GN Wu Wei W Kiru Louise L Delaidelli Alberto A Sotillo Elena E Silberstein John L JL Geraghty Anna C AC Banuelos Allison A Radosevich Molly Thomas MT Dhingra Shaurya S Heitzeneder Sabine S Tousley Aidan A Lattin John J Xu Peng P Huang Jing J Nasholm Nicole N He Andy A Kuo Tracy C TC Sangalang Emma R B ERB Pons Jaume J Barkal Amira A Brewer Rachel E RE Marjon Kristopher D KD Vilches-Moure Jose G JG Marshall Payton L PL Fernandes Ricardo R Monje Michelle M Cochran Jennifer R JR Sorensen Poul H PH Daldrup-Link Heike E HE Weissman Irving L IL Sage Julien J Majeti Ravindra R Bertozzi Carolyn R CR Weiss William A WA Mackall Crystal L CL Majzner Robbie G RG

Nature medicine 20220113 2

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2<sup>+</sup> malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoin ...[more]

PMID: 35027753

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Project description:BackgroundTargeting oncogenic histone modification by histone deacetylase inhibitors (HDACis) demonstrates promising prospects in clinical cancer treatment, whereas a notable proportion of patients cannot benefit from HDACi therapy. This study aims to explore how HDACi influences the tumor microenvironment, in order to identify potential targets for reversing the resistance to HDACi therapies.MethodsMacrophage infiltration was compared between HDACi-responding and HDACi-nonresponding cancer patients. The impact of HDACis on the phagocytic capacity of macrophages was investigated through macrophage-tumor cell co-culture system. CD47 expression in tumor cell lines and patient-derived organoids was evaluated by quantitative polymerase chain reaction (QPCR) and flow cytometry. Mechanistic studies were conducted through co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP). The synergistic effect of HDACis and CD47 neutralizing antibody was assessed in subcutaneous murine tumor models. Bioinformatics approaches were adopted to analyze how macrophage infiltration determines the prognostic significance of CD47 expression in cancer patients.ResultsHigh macrophage infiltration is a determinant of therapeutic non-response to HDACi, cancer patients who did not respond to HDACi exhibit massive infiltration of tumor-associated macrophages (TAMs). TAM depletion reversed the resistance to HDACi therapy. Mechanistically, HDACi impaired the phagocytic capacity of macrophages against tumor cells through epigenetically upregulating CD47 expression. Reciprocally, HDACi-upregulated CD47 polarized macrophages towards a pro-tumor M2 phenotype through SIRPα ligation. In tumor-bearing mice, HDACi monotherapy only marginally delayed tumor progression, while the concurrent neutralization of CD47 exhibited potent anti-tumor effect through re-educating TAMs towards a tumoricidal phenotype. In cancer patients, CD47 was found to determine the prognostic significance of TAMs.ConclusionsOur study offers a rationale for targeting macrophage infiltration or blocking CD47 to sensitize HDACi therapies in cancer patients.

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Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

Publications

Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

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