4.7 Article

T cells, particularly activated CD4+ cells, maintain anti-CD20-mediated NK cell viability and antibody dependent cellular cytotoxicity

期刊

CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 71, 期 2, 页码 237-249

出版社

SPRINGER
DOI: 10.1007/s00262-021-02976-7

关键词

NK cell; ADCC; Rituximab; T cell; Bispecific antibody

资金

  1. National Institute of Health [P50 CA097274, P30 CA86862]

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The study found that T cell help, mainly mediated by local production of IL2, plays a significant role in enhancing NK cell-mediated antibody-dependent cellular cytotoxicity and viability. Activating T cells can improve the efficacy of anti-CD20 and other mAb therapies, particularly when NK-mediated antibody-dependent cellular cytotoxicity is the primary mechanism of action.
Anti-CD20 monoclonal antibody (mAb) therapy is a mainstay of therapy for B cell malignancies, however many patients fail to respond or eventually develop resistance. The current understanding of mechanisms responsible for this resistance is limited. When peripheral blood mononuclear cells of healthy donors were cultured with Raji cells for 7 days, rituximab (RTX) induced NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), enhanced NK cell viability and increased or maintained NK expression of CD56, CD16, CD57 and KIR. T cells, mainly CD4(+), mediated these changes in a contact-dependent manner, with local T cell production of IL2 playing a central role. Similar findings were found when autologous B cells were used as target cells demonstrating the need for T cell help was not due to allogenic reaction. Results with other anti-CD20 and anti-EGFR antibodies were consistent. Small numbers of T cells activated by anti-CD3/CD28 beads or bispecific antibody enhanced RTX-mediated NK cell ADCC, viability and phenotypical changes. Pathway analysis of bulk NK cell mRNA sequencing after activation by RTX with and without T cells was consistent with T cells maintaining the viability of the activated NK cells. These findings suggest T cell help, mediated in large part by local production of IL2, contributes to NK cell ADCC and viability, and that activating T cells in the tumor microenvironment, such as through the use of anti-CD3 based bispecific antibodies, could enhance the efficacy of anti-CD20 and other mAb therapies where NK-mediated ADCC is a primary mechanism of action.

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