Implication of combined PD-L1/PD-1 blockade with cytokine-induced killer cells as a synergistic immunotherapy for gastrointestinal cancer

Abstract

Cytokine-induced killer (CIK) cells represent a realistic approach in cancer immunotherapy with confirmed survival benefits in the context of metastatic solid tumors. However, therapeutic effects are limited to a fraction of patients. In this study, immune-resistance elements and ideal combination therapies were explored. Initially, phenotypic analysis was performed to document CD3, CD56, NKG2D, DNAM-1, PD-L1, PD-1, CTLA-4, TIM-3, 2B4, and LAG-3 on CIK cells. Upon engagement of CIK cells with the tumor cells, expression of PD-1 on CIK cells and PD-L1 on both cells were up-regulated. Over-expression of PD-L1 levels on tumor cells via lentiviral transduction inhibited tumoricidal activity of CIK cells, and neutralizing of PD-L1/PD-1 signaling axis could enhance their tumor-killing effect. Conversely, blockade of NKG2D, a major activating receptor of CIK cells, largely caused dysfunction of CIK cells. Functional study showed an increase of NKG2D levels along with PD-L1/PD-1 blockade in the presence of other immune effector molecule secretion. Additionally, combined therapy of CIK infusion and PD-L1/PD-1 blockade caused a delay of in vivo tumor growth and exhibited a survival advantage over untreated mice. These results provide a preclinical proof-of-concept for simultaneous PD-L1/PD-1 pathways blockade along with CIK infusion as a novel immunotherapy for unresectable cancers.

Dynamic Immune Activation: Upregulation of Immune Inhibitory Pathways in Gastric Cancer

“…This mechanistic study demonstrated that up-regulation of these three inhibitory elements in the tumor microenvironment depended just on the presence of effector T cell infiltration [12]. Previous experiment also showed an immediate increase in PD-L1 expression on the gastric tumor cells once co-cultured with immune cells [13]. Strikingly, in gastric cancer specimens, it was also revealed that, high expression of these inhibitory molecules including PD-L1, PD-1, CTLA-4, T-cell immunoglobulin domain and mucin domain 3 (TIM-3), IDO1, LAG-3, transforming growth factor-β (TGF-β), interleukin-10 (IL-10), and Foxp3 positively correlated with the levels of IFN-gamma, without an exception.…”

Knockdown of PD-L1 in Human Gastric Cancer Cells Inhibits Tumor Progression and Improves the Cytotoxic Sensitivity to CIK Therapy

“…In our study, we have shown that the cytotoxic activity of the CIK cells against LV-PD-L1-siRNA group was markedly higher than that of LV-NC group, under the same conditions, in both human gastric cancer cell lines. This led us to suggest that PD-L1 detection could also have a role in being used as an essential marker for the selection of CIK therapy in gastric cancer patients [14]. …”

“…Moreover, the PD-L1 expression status has equally been used as an important marker to evaluate the effect of anti-PD-1 targeted therapy against certain advanced human cancers [12-14]. In addition, PD-L1 expression in tumor cells not only dampens the T-cell mediated anti-tumor response, but also regulates the biological behaviors of the tumor cells, such as proliferation, apoptosis, migration, invasion, along with resistance to radiotherapy and chemotherapy [15-19].…”

Cytokines as potential combination agents with PD‐1/PD‐L1 blockade for cancer treatment

“…There is considerable evidence that combining PD‐1‐targeted therapies with other immunotherapy agents will cause improved outcomes compared to monotherapy activity. For this purpose, several cytokines are being tested to overcome the resistance mechanisms by expanding and reactivating effector NK and T lymphocytes and promoting the shift of lymphocytes to the tumor environment (Dai et al, 2016; Desbois et al, 2016; Garris et al, 2018; Zhao et al, 2018). Cytokine‐based drugs combined with PD‐1/PD‐L1 inhibitors have had some excitement clinical results in several ongoing clinical trials (as shown in Table 2).…”