NK Cell–Mediated Antitumor Effects of a Folate-Conjugated Immunoglobulin Are Enhanced by Cytokines

Abstract

Optimally effective antitumor therapies would not only activate immune effector cells, but engage them at the tumor. Folate-conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor–expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR) overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by NK cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P < 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNγ, MIP-1α, and RANTES in response to F-IgG–coated KB target cells in the presence of the NK cell–activating cytokine IL12, and these coculture supernatants induced significant T cell chemotaxis P < 0.001). F-IgG–coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P = 0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo. Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

“…Research performed on the animal leukemia model proved the intratumoral localization and antitumor action of F-IgG, as well as improvement of its actions by IL12. Thus, F-IgG can stimulate an immune response against FR-positive tumor cells that is controlled by NK cells and can be increased by cytokine administration [215].…”

Harnessing Engineered Immune Cells and Bacteria as Drug Carriers for Cancer Immunotherapy

“…The biomaterial-based drug delivery systems discussed here are capable of reversing immunosuppressive “cold tumors” into immunoactive “hot tumors” through various self-produced immunostimulatory cytokines or adjuvants to boost antitumor immunity in the TME and sensitize tumors to other chemical/biological therapeutics, which is their own function not available in other ordinary nanocarrier materials. Cytokines secreted from immune cells, such as IL-4 and IL-12, have been verified that they can further act on other immune cells around to maintain their antitumor efficiency and avoid immune dysfunction and exhaustion caused by factors in the TME. The nanovesicles derived from them also maintain the immunomodulation capacity .…”

Polymeric biomaterial-inspired cell surface modulation for the development of novel anticancer therapeutics

“…In terms of advantages, the FA moiety would be applied for cell surface modification that could enhance the cell–cell interaction. Application of FA conjugated to immunoglobulin (IgG) applied activates NK cells, and selectively binds to FR overexpressed cancer cells [ 44 ]. The FA–hepten conjugate is applied to the immune cell to selectively kill cancer cells.…”