Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.

Aims and background: The programmed death-1-ligand 1 (PD-L1) has been recently suggested to play a pivotal role in the immune evasion of tumors from host immune system. In the study, we tried to reveal the clinical significance of PD-L1 in patients with non-small cell lung cancer (NSCLC), which is one of the most aggressive and intractable malignant tumors. Methods and study design: PD-L1 expression in 120 NSCLC tissue specimens and 10 benign control samples embedded with wax were retrospectively detected by immunohistochemistry. Results: No PD-L1 was detected in the 10 benign controls, whereas 57.5% of NSCLC tissue specimens showed PD-L1 expression. There was no relationship between PD-L1 expression and patient age, gender or histopathological type. However, PD-L1 expression was significantly correlated to the degree of tumor cell differentiation, stage of tumor node metastasis (TNM) and patient survival. Poor tumor cell differentiation and advanced TNM stage were related to higher PD-L1 expression. PD-L1-negative NSCLC patients had longer overall 5-year survival than PD-L1-positive patients (P <0.0001). PD-L1 status was a significant independent prognostic factor of NSCLC (χ² = 18.153, RR = 2.946, P <0.001). Conclusions: Up-regulated PD-L1 expression in NSCLC is related to the degree of tumor cell differentiation and TNM stage. PD-L1 status may be a new predictor of prognosis for patients with NSCLC.

In addition to the role of programmed cell death ligand 1 (PD-L1) in facilitating tumour cells escape from immune surveillance, it is considered as a crucial effector in transducing intrinsic signals to promote tumour development. Our previous study has pointed out that PD-L1 promotes non-small cell lung cancer (NSCLC) cell proliferation, but the mechanism remains elusive. Here we first demonstrated that PD-L1 expression levels were positively correlated with p-MerTK levels in patient samples and NSCLC cell lines. In addition, PD-L1 knockdown led to the reduced phosphorylation level of MerTK in vitro. We next showed that PD-L1 regulated NSCLC cell proliferation via Gas6/MerTK signaling pathway in vitro and in vivo. To investigate the underlying mechanism, we unexpectedly found that PD-L1 translocated into the nucleus of cancer cells which was facilitated through the binding of Karyopherin β1 (KPNB1). Nuclear PD-L1 (nPD-L1), coupled with transcription factor Sp1, regulated the synthesis of Gas6 mRNA and promoted Gas6 secretion to activate MerTK signaling pathway. Taken together, our results shed light on the novel role of nPD-L1 in NSCLC cell proliferation and reveal a new molecular mechanism underlying nPD-L1-mediated Gas6/MerTK signaling activation. All above findings provide the possible combinational implications for PD-L1 targeted immunotherapy in the clinic.