STAT3 inhibition reduced PD‐L1 expression and enhanced antitumor immune responses

Abstract

Colon cancer is one the most common diagnosed cancers in America and Europe. Signal transducer and activator of transcription 3 (STAT3) in colon cancer is associated with proliferation of the tumor cells and suppression of immune responses. STAT3 activation upregulates the transcription of many suppressor genes, including programmed death‐ligand 1 (PD‐L1). This study was aimed to investigate the effect of STAT3 inhibition in a colon cancer cell line, HCT‐15, and particularly in presence of samples obtained from the patients suffering from colon cancer. In this project, the expression of PD‐L1 and apoptosis‐related proteins were assessed following STAT3 inhibition, using FLLL32, in HCT‐15 cells. To evaluate the effects of STAT3 inhibition on immune response, lymphocytes from 20 men with Stage III colon cancer and 20 healthy donors were cocultured with HCT‐15 cells in presence or absence of STAT3 inhibitor. Then, T regulatory (T‐reg) cell evaluation and intracellular cytokine staining (ICS) were performed using flowcytometry to assess the T‐reg and T helper (Th) subset cytokines following STAT3 inhibition. STAT3 inhibition suppressed PD‐L1 expression and induced apoptosis in HCT‐15 cells. The population of T‐reg cells in patients with colon cancer significantly decreased after treatment with STAT3 inhibitor. ICS revealed that STAT3 inhibition promotes Th1 protective immune responses. These findings suggest that STAT3 inhibition through either induction of apoptosis in the colon cancer cells and/or activation of efficient immune responses can lead to overcome cancer‐induced immune tolerance.

The JAK/STAT signaling pathway: from bench to clinic

“…FLLL32 inhibited PD-L1 expression, decreased the number of Treg cells, and promoted Th1-protective immune responses. 515 Besides, FLLL32 inhibited STAT3 phosphorylation induced by IFNα and IL-6 in breast cancer cells and retarded tumor growth in chicken embryo and mouse models. 516 Resveratrol: Resveratrol, a natural polyphenolic stilbenoid, is found in grapes, mulberries, peanuts, rhubarb, etc.…”

An aberrant STAT pathway is central to COVID-19

“…The virus may then migrate into the interstitium and enter capillaries, where it could infect endothelial cells. The infection causes aberrant STAT3 regulation in these endothelial cells and may also induce PD-L1 activity, as demonstrated for some cancer cells with constitutively active STAT3 [149,150]. In the critical stages of COVID-19, the PD1/PD-L1-induced death of T cells becomes systemic, resulting in severe T cell lymphopenia (12, Fig.…”

Signal transducer and activator of transcription 3 signaling in tumor immune evasion

“…One mechanism of STAT3-mediated tumor immune evasion is the interaction of STAT3 with immune checkpoints. For example, STAT3 signaling in a colorectal cancer cell line, HCT15 promotes the function of programmed death ligand 1 (PD-L1) and upregulates the expression of anti-apoptotic molecules such as B-cell lymphoma (Bcl)-2 and Bcl-xl on tumor cells (Jahangiri, Dadmanesh, & Ghorban, 2020). PD-L1 upregulation in natural killer/T-cell lymphoma can enhance tumor immune evasion (Jahangiri, Dadmanesh, & Ghorban, 2020).…”