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.

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Breast cancer (BC) is the most prevalent diagnosed cancer among women. Herceptin blocks the effects of Her‐2 and tumour cell growth. Despite many achievements using Herceptin in Her‐2+ invasive BC treatment, there are treatment failures and resistances. The signal transducer and activator of transcription 3 (STAT3) is persistently activated in BC and is associated with immune suppression and tumour cell proliferation. We evaluated whether STAT3 inhibition could increase Herceptin impact on in vitro reduction of immune checkpoint inhibitors and polarize T cells to a protective immune response. We treated SK‐BR‐3 cells with Herceptin and the STAT3‐inhibitor (FLLL32) and assessed the apoptosis and expression of apoptosis‐related proteins, VEGF, Her‐2 and apoptosis targets of STAT3. PBMCs were isolated from healthy donors and co‐cultured with SK‐BR‐3 cells in the presence or absence of Herceptin and FLLL32. PD‐L1, CTLA‐4, TIM‐3 and T‐cell intracellular cytokines were then evaluated. Our results demonstrated that STAT3 inhibition and Herceptin increased SK‐BR‐3 cell apoptosis, significantly. STAT3 inhibition through combination treatment had a more significant effect on regulating PD‐1, TIM‐3 and CTLA‐4 expression on PBMCs. Alternatively, the combination of FLLL32 and Herceptin promoted T helper‐1 protective immune response. The combination of FLLL32 and Herceptin suppress the expression of immune checkpoints and provoke the T‐helper1 immune response in lymphocytes. Our analysis indicates STAT3 as a promising target that improves Herceptin's role in breast cancer cell apoptosis.