Abstract 1687: T cells are required to maintain anti-CD20-mediated NK cell responses in vitro

Zhaoming Wang; George J. Weiner

doi:10.1158/1538-7445.AM2021-1687

Abstract Purpose: Anti-CD20 monoclonal antibodies, beginning with rituximab (RTX), are a mainstay of therapy for B cell malignancies. Despite their remarkable clinical efficacy, many patients fail to respond or develop resistance to anti-CD20 containing therapy. A better understanding of the mechanisms by which anti-CD20 antibodies mediate their anti-tumor effects is critical if we are to build further on what is already a remarkable success story. Experimental procedures: Various subsets of healthy donor peripheral blood mononuclear cells (PBMCs) were cocultured in vitro with Raji cells and RTX or trastuzumab (TRA) as a control antibody for up to 7 days. The number of remaining Raji cells, NK cells and phenotype of NK cells was determined. Results: When unfractionated PBMCs were cultured with Raji cells for 1 week, RTX depleted Raji cells and enhanced NK cell numbers compared to TRA. In such cultures, RTX also induced changes in NK cell phenotype including a shift from CD56dim to CD56bright and increased expression of CD16, CD57 and KIR. These changes were dependent on T cells. Depletion of T cells, largely CD4, suppressed elimination of Raji cells, NK cell viability and the change in NK cell phenotype. Cell to cell contact was required, as the ability of T cells to support NK cell cytotoxicity, viability and phenotypic change was lost when T cells were separated from other cells in a transwell assay. T cell activation with anti-CD3/CD28 beads enhanced the ability of T cells to support RTX-mediated NK cell responses, with concentrations of activated T cells as low as 1% being adequate to provide T cell help to NK cells. Similar results were seen when obinutuzumab was used instead of RTX and when autologous B cells were used as target cells instead of Raji cells demonstrating the observed T cell effect was not secondary to an allogenic response by T cells to Raji cells. Conclusion: In longer term in vitro culture, anti-CD20 induces lysis of target B cells, preserves NK cell viability, and induces CD56dim to CD56bright transition and CD16 recovery in a T cell dependent manner. This T cell help requires cell-to-cell contact with NK cells and is enhanced following T cell activation. Ongoing studies are exploring the precise mechanisms by which T cells support NK cells, and whether similar changes are observed in patients. These findings could lead to evaluation of a combination of anti-CD20 therapy and T cell activation as a strategy for overcoming resistance to anti-CD20 therapy. Citation Format: Zhaoming Wang, George J. Weiner. T cells are required to maintain anti-CD20-mediated NK cell responses in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1687.

Abstract 1687: T cells are required to maintain anti-CD20-mediated NK cell responses in vitro

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