Abstract
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.
Highlights
Therapeutic anti-tumor monoclonal antibody became a standard and important component of cancer therapy starting with rituximab (RTX), an anti-CD20 mAb
Human NK cells are typically defined as CD3−CD56+ lymphocytes and are divided into two subsets: CD56dim and CD56bright. CD56dim NK cells make up the majority (~ 90%) of circulating NK cells and express high levels of CD16[6]
Initial studies evaluated the impact of RTX on antibody-dependent cellular cytotoxicity (ADCC) as well as the number and phenotype of NK cells in longer term cultures of Peripheral blood mononuclear cells (PBMC) and Raji cells
Summary
Therapeutic anti-tumor monoclonal antibody (mAb) became a standard and important component of cancer therapy starting with rituximab (RTX), an anti-CD20 mAb. NK cell-mediated ADCC is believed to play an important role in mediating the anti-tumor activity of RTX in humans[1,2,3,4,5]. CD56dim NK cells make up the majority (~ 90%) of circulating NK cells and express high levels of CD16[6]. They are considered to be the main effectors for ADCC. The accepted paradigm is that C D56dim NK are more mature and evolve from CD56bright NK[7] During this differentiation from CD56bright to CD56dim, NK cells decrease the expression of c-kit, CD127 and CD62L while increasing the expression of CD57, KIRs and CD16[8]. The median half-life of RTX in non-Hodgkin lymphoma patients
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