Colorectal cancer (CRC) is one of the top three malignant tumors in terms of morbidity, and the limited efficacy of existing therapies urges the discovery of potential treatment strategies. Immunotherapy gradually becomes a promising cancer treatment method in recent decades; however, less than 10% of CRC patients could really benefit from immunotherapy. It is pressing to explore the potential combination therapy to improve the immunotherapy efficacy in CRC patients. It is reported that Farnesoid X receptor (FXR) is deficiency in CRC and associated with immunity. Herein, we found that GW4064, a FXR agonist, could induce apoptosis, block cell cycle, and mediate immunogenic cell death (ICD) of CRC cells in vitro. Disappointingly, GW4064 could not suppress the growth of CRC tumors in vivo. Further studies revealed that GW4064 upregulated PD-L1 expression in CRC cells via activating FXR and MAPK signaling pathways. Gratifyingly, the combination of PD-L1 antibody with GW4064 exhibited excellent anti-tumor effects in CT26 xenograft models and increased CD8+ T cells infiltration, with 33% tumor bearing mice cured. This paper illustrates the potential mechanisms of GW4064 to upregulate PD-L1 expression in CRC cells and provides important data to support the combination therapy of PD-L1 immune checkpoint blockade with FXR agonist for CRC patients.
© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.

The elevated expression of immune checkpoints by the tumor microenvironment is associated with poor prognosis in several cancers due to the exhaustion of tumor-infiltrating lymphocytes (TILs), and the effective suppression of the expression of these genes is key to reversing the exhaustion of TILs. Herein, we determined that serine/arginine-rich splicing factor 2 (SRSF2) is a target for blocking the tumor microenvironment-associated immunosuppressive effects. We found that the expression of SRSF2 was increased in exhausted T cells and that SRSF2 was involved in multiple immune checkpoint molecules mediating TILs' exhaustion. Furthermore, SRSF2 was revealed to regulate the transcription of these immune checkpoint genes by associating with an acyl-transferases P300/CBP complex and altering the H3K27Ac level near these genes, thereafter influencing the recruitment of signal transducer and activator of transcription 3 (STAT3) to these gene promoters. Collectively, our data indicated that SRSF2 functions as a modulator of the anti-tumor response of T cells and may be a therapeutic target for reversing the exhaustion of TILs.

Most of the patients with lung cancer are diagnosed at advanced stage, and they often lose the opportunity of surgical therapy, most of whom fail to reach good prognosis after chemotherapy. Recently, a few clinical studies have confirmed the role of adoptive T-cell transfer in the maintenance therapy of cancer patients. Here, we provided statistical insights into the role of CIKs in advanced lung cancer from three different levels, cell model (in vitro co-culture system), mice model (in situ lung cancer), and clinical research (in lung cancer patients of different progression stages). We optimized the components of supplements and cytokines on activating and expanding CIK cells. Based on this, we explored a new serum-free medium for in vitro activation and expansion of CIK cells. Moreover, we found that activated CIK cells could efficiently kill lung cancer cells in cell-to-cell model in vitro and significantly reduce the tumor growth in mice. For the clinical research, the OS rates of patients received combination of chemotherapy and CIK treatment were significantly improved compared to the OS rates of patients only received chemotherapy. Additionally, CIK therapy represented good toleration in our study. All the results suggested that combination of immunotherapy with traditional therapy will be a feasible and promising method for the treatment of lung cancer.