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

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.

CD4+ T cells in cancer

“…NK cells have demonstrated potent anti-tumor efficacy by directly killing cancer cells in preclinical animal models and clinical settings 41,42 . CD4 + T cell derived IL-2 also maintains NK cells for targeting of antibody opsonized tumor cells, such as anti-CD20 antibody coated B cell lymphomas 43 . Furthermore, myeloid cell activation by CD4 + T cell produced IFN- and TNF- leads to tumor cell killing, probably by induced nitric oxide production 44 , upon TAA uptake and presentation by macrophage populations in the TME 45 .…”

Validation of CDC45 as a novel biomarker for diagnosis and prognosis of gastric cancer

“…Early studies have provided confirmation of the anti-tumor function of NK cells in defending against tumor metastases ( Larsen, Gao & Basse, 2014 ). Activated CD4+ T cells Additionally, recent evidence has demonstrated that activated CD4 + T cells contribute to the maintenance of NK cell viability and their ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) via local IL-2 production ( Wang et al, 2022 ). Furthermore, CD4 + T cells have long been recognized for their critical roles in coordinating of innate and antigen-specific immune responses ( Speiser et al, 2023 ).…”

The role of CD4+ T cells in tumor and chronic viral immune responses

“…191,192 Similarly, CD4 + T cell-derived IFN-γ mediates an increase in tumoricidal effectors, monocytemacrophages, which secrete NO to induce remote inflammatory cell death in IFN-unresponsive, MHC-deficient tumor cells. 193 Second, IL-2 produced by CD4 + T cells has been proved to associated with the maintenance and the activation of NK cells, [194][195][196] which could present antitumor effects through direct killing functions in murine models and clinical patients. 197,198 Additionally, it has been reported that CD4 + T cells play a vital role in the induction of humoral responses (Figure 3B).…”

“…Second, IL‐2 produced by CD4 + T cells has been proved to associated with the maintenance and the activation of NK cells, 194 , 195 , 196 which could present antitumor effects through direct killing functions in murine models and clinical patients. 197 , 198 …”