Systems pharmacology dissection of Epimedium targeting tumor microenvironment to enhance cytotoxic T lymphocyte responses in lung cancer

Abstract

The clinical notably success of immunotherapy fosters an enthusiasm in developing drugs by enhancing antitumor immunity in the tumor microenvironment (TME). Epimedium , is a promising herbal medicine for tumor immunotherapy due to the pharmacological actions in immunological function modulation and antitumor. Here, we developed a novel systems pharmacology strategy to explore the polypharmacology mechanism of Epimedium involving in targeting TME of non-small cell lung cancer (NSCLC). This strategy integrates the active compounds screening, target predicting, network pharmacology analysis and onco-immune interacting to predict the potential active compounds that trigger the antitumor immunity. Icaritin (ICT), a major active ingredient of Epimedium , was predicted to have good drug-like properties and target immune microenvironment in NSCLC via regulating multiple targets and pathways. Then, we evidenced that the ICT effectively inhibited tumor growth in LLC tumor-bearing mice and increases the infiltration of CD8+ T cells in TME. In addition, we demonstrated that ICT promotes infiltration of CD8 + T cells in TME by downregulating the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulating chemotaxis (CXCL9 and CXCL10). Overall, the systems pharmacology strategy offers an important paradigm to understand the mechanism of polypharmacology of natural products targeting TME.

Prognostic value of the pretreatment systemic immune-inflammation index in patients with prostate cancer: a systematic review and meta-analysis

“…Lymphocytes, especially T-lymphocytes, are known to be an effective tool for the antitumor immune response [ 61 ]. Promoting infiltration of T-lymphocytes in the TME by downregulating immunosuppressive cytokines (IL10, IL6) has been reported as an effective way to enhance antitumor immunity [ 62 ]. According to several publications, infiltration of more lymphocytes in the TME is correlated with better survival of cancer patients [ 63 ], which indicates that lymphocyte count is associated with the immune escape of cancer cells.…”

M2‐polarization‐related CNTNAP1 gene might be a novel immunotherapeutic target and biomarker for clear cell renal cell carcinoma

“…42,43 TME had been the focus of cancer pathogenesis and treatment. [44][45][46] Currently, it was well recognized that CAFs, [47][48][49][50] Tregs, [51][52][53] and MDSCs [54][55][56][57] were characterized as tumor-promoting TIICs, while eosinophils 58,59 were considered as one of the tumor suppressor cells. The current work revealed the relationship between CNTNAP1 and TIICs, especially M2-macrophage, for the first time.…”

“…TME was important to the prognosis and treatment of various cancers 42,43 . TME had been the focus of cancer pathogenesis and treatment 44–46 . Currently, it was well recognized that CAFs, 47–50 Tregs, 51–53 and MDSCs 54–57 were characterized as tumor‐promoting TIICs, while eosinophils 58,59 were considered as one of the tumor suppressor cells.…”

Icaritin induces apoptosis and downregulates RhoA/ROCK pathway in the A549 adenocarcinoma cell line

“…In vivo studies revealed that ICT can enhance CD8+ T cell infiltration. The chemokines produced by T-cells, can modify the tumour microenvironment and improve the patient outcome [18]. Several studies showed that icaritin can limit the proliferation rate inducing cell cycle arrest.…”

“…Control of cell motility in the actin cytoskeleton creates the potential for regulating tumour cell metastasis [8]. The Rho family of GTPases is a family of small monomeric G proteins that belong to the Ras superfamily of GTPases and comprises more than 50 members that share several common features: their molecular weight (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), their C-terminal polyisoprenylation region, and the property to bind to and hydrolase guanine nucleotides [9]. Rho GTPases bind to a wide range of effector proteins and play central roles in the regulation of the actin and microtubule cytoskeletons and gene transcription [10].…”