Neem Leaf Glycoprotein Partially Rectifies Suppressed Dendritic Cell Functions and Associated T Cell Efficacy in Patients with Stage IIIB Cervical Cancer

Abstract

Myeloid-derived dendritic cells (DCs) generated from monocytes obtained from stage IIIB cervical cancer (CaCx IIIB) patients show dysfunctional maturation; thus, antitumor T cell functions are dysregulated. In an objective to optimize these dysregulated immune functions, the present study is focused on the ability of neem leaf glycoprotein (NLGP), a nontoxic preparation of the neem leaf, to induce optimum maturation of dendritic cells from CaCx IIIB patients. In vitro NLGP treatment of immature DCs (iDCs) obtained from CaCx IIIB patients results in upregulated expression of various cell surface markers (CD40, CD83, CD80, CD86, and HLA-ABC), which indicates DC maturation. Consequently, NLGP-matured DCs displayed balanced cytokine secretions, with type 1 bias and noteworthy functional properties. These DCs displayed substantial T cell allostimulatory capacity and promoted the generation of cytotoxic T lymphocytes (CTLs). Although NLGPmatured DCs derived from CaCx monocytes are generally subdued compared to those with a healthy monocyte origin, considerable revival of the suppressed DC-based immune functions is noted in vitro at a fairly advanced stage of CaCx, and thus, further exploration of ex vivo and in vivo DC-based vaccines is proposed. Moreover, the DC maturating efficacy of NLGP might be much more effective in the earlier stages of CaCx, where the extent of immune dysregulation is less and, thus, the scope of further investigation may be explored.Cervical cancer (CaCx) is the second most common type of tumor worldwide, and its incidence is disproportionately high (Ͼ80%) in the developing world (35). It remains an important health problem for women, especially in underserved and socioeconomically backward classes (29). Immunotherapy with mature monocyte-derived dendritic cells (DCs) pulsed with human papillomavirus type 16 or 18 (HPV16/18) E7 oncoprotein antigens is a promising approach in treating this disease (32). These alternate therapeutic approaches are aimed toward controlling late-stage detection and preventing recurrence (31), an arena where application of traditional therapeutic approaches like radical surgery or radiotherapy is difficult. DCs are extremely potent antigen-presenting cells (APC) that function in vitro and in vivo to initiate T lymphocyte responses to antigens (14). The ability of DCs to stimulate T cells is attributed to their dichotomous nature as immature DCs (iDCs) and mature DCs (mDCs) (30). Immature DCs effectively capture antigens but lack full T cell stimulatory activity and are sensitive to the immunosuppressive effects of an immunoregulatory cytokine, interleukin-10 (IL-10). In contrast, mature DCs exhibit an enhanced level of antigen presentation, full T cell stimulatory activity, production of a type 1 cytokine, IL-12, and low production of a type 2 cytokine, IL-10 (36).In the last few years, a multitude of diagnostic studies have shown a strong immunosuppressive state of the cervical epithelium, which is one major reason for the fragile health of cervical cancer patient...

Neem Leaf Glycoprotein Activates CD8+ T Cells to Promote Therapeutic Anti-Tumor Immunity Inhibiting the Growth of Mouse Sarcoma

“…These in vivo results are in accordance with our in vitro data, where NLGP showed efficacy to enhance the CD8 + T cells within human [21] and mouse [24] mononuclear cells. NLGP enhances antigen processing and presentation through different antigen presenting cells (APCs) and upregulates the expression of MHCs and co-stimulatory molecules [20], [22], [28]. NLGP significantly enhances the secretion of IL-12 from macrophages/dendritic cells [20] and this IL-12 regulates T cell functions, e.g.…”

“…NLGP can activate T cells [21], [22], NK cells [23], inhibit Tregs [24], promote type 1 cytokine microenvironment [25], [26] and rectify altered chemokine signaling [27], [28], thereby, inducing antigen-specific tumor cell killing [19]–[21], [29]. Here, for the first time, we have tested the therapeutic potential of NLGP in sarcoma tumor model.…”

Neem components as potential agents for cancer prevention and treatment

“…Transcription factor T-bet-associated with Th1 immune responses is also induced by NLGP in peripheral immune cells [61]. In vitro treatment of matured DCs isolated from patients with stage IIIB cervical cancer (CaCx IIIB) with NLGP demonstrates cytokine release profile biased towards Th1 immune response and activated cytotoxic T lymphocytes [62]. The consistency between the in vivo immune activating actions of NLGP and NLE thus confirms that NLGP is, at least partially, responsible for the immunomodulating functions of NLE.…”

The immunoregulatory effects of Chinese herbal medicine on the maturation and function of dendritic cells

“…Roy et al, 2011). The purified Glycyrrhizin increased expressions of CD40, CD80, CD86, CD83 and MHC II and the production of IL-12 and IL-10, and decreased the production of TNF-α (Hua et al, 2012).…”

“…leaf glycoprotein (NLGP) treatment upregulated the expressions of CD40, CD83, CD80, CD86, HLA-ABC and the production of IL-12 in iDCs obtained from CaCx IIIB patients. NLGP-matured DCs displayed substantial T cell allostimulatory capacity and promoted the generation of CTLs (Roy et al, 2011).…”