Modulating tumor infiltrating myeloid cells to enhance bispecific antibody-driven T cell infiltration and anti-tumor response Journal Article
| Authors: | Park, J. A.; Wang, L.; Cheung, N. K. V. |
| Article Title: | Modulating tumor infiltrating myeloid cells to enhance bispecific antibody-driven T cell infiltration and anti-tumor response |
| Abstract: | Background: Tumor microenvironment (TME) is a dynamic cellular milieu to promote tumor angiogenesis, growth, proliferation, and metastasis, while derailing the host anti-tumor response. TME impedes bispecific antibody (BsAb) or chimeric antigen receptor (CAR)-driven T cells infiltration, survival, and cytotoxic efficacy. Modulating tumor infiltrating myeloid cells (TIMs) could potentially improve the efficacy of BsAb. Methods: We evaluated the effects of TIM modulation on BsAb-driven T cell infiltration into tumors, their persistence, and in vivo anti-tumor response. Anti-GD2 BsAb and anti-HER2 BsAb built on IgG-[L]-scFv platform were tested against human cancer xenografts in BALB-Rag2−/−IL-2R-γc-KO (BRG) mice. Depleting antibodies specific for polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic MDSC (M-MDSC), and tumor associated macrophage (TAM) were used to study the role of each TIM component. Dexamethasone, an established anti-inflammatory agent, was tested for its effect on TIMs. Results: BsAb-driven T cells recruited myeloid cells into human tumor xenografts. Each TIM targeting therapy depleted cells of interest in blood and in tumors. Depletion of PMN-MDSCs, M-MDSCs, and particularly TAMs was associated with enhanced T cell infiltration into tumors, significantly improving tumor control and survival in multiple cancer xenograft models. Dexamethasone premedication depleted monocytes in circulation and TAMs in tumors, enhanced BsAb-driven T cell infiltration, and anti-tumor response with survival benefit. Conclusion: Reducing TIMs markedly enhanced anti-tumor effects of BsAb-based T cell immunotherapy by improving intratumoral T cell infiltration and persistence. TAM depletion was more effective than PMN- or M-MDSCs depletion at boosting the anti-tumor response of T cell engaging BsAb. © 2021, The Author(s). |
| Keywords: | dexamethasone; immunotherapy; t cell; tumor microenvironment; tumor-associated macrophage; bispecific antibody; human epidermal growth factor receptor 2 (her2); myeloid-derived suppressor cell; disialogangliosides; ex vivo bispecific antibody armed t-cells (eats); tumor infiltrating myeloid cell |
| Journal Title: | Journal of Hematology & Oncology |
| Volume: | 14 |
| ISSN: | 1756-8722 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2021-09-08 |
| Start Page: | 142 |
| Language: | English |
| DOI: | 10.1186/s13045-021-01156-5 |
| PROVIDER: | scopus |
| PMCID: | PMC8424962 |
| PUBMED: | 34496935 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2021 -- Source: Scopus |
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