Immunologic Features of Patients With Advanced Hepatocellular Carcinoma Before and During Sorafenib or Anti-programmed Death-1/Programmed Death-L1 Treatment.

INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Today, a promising treatment strategy is focused on the enhancement of antitumor immune responses by immune checkpoint modification. However, as only 20% of patients with HCC are responders, identification of predictive factors is urgently required. Therefore, for the first time, the features of the intrahepatic and circulating immune system in patients with advanced-stage HCC, before and during the treatment, were analyzed. METHODS: We collected fresh HCC biopsies, along with adjacent tumor-free liver tissues and peripheral blood samples, from 21 patients with advanced HCC. Furthermore, we performed an extensive immunomonitoring of patients with HCC treated with sorafenib or programmed death (PD)-1/PD-L1 pathway blockade using multiparametric flow cytometry. RESULTS: We observed that regardless of the treatment, low baseline intratumoral CD4/CD8 T-cell ratio was associated with better overall survival (P = 0.0002). The baseline frequency of intratumoral PD-1 CD8 T cells was significantly lower in patients responding to sorafenib treatment than in the nonresponders (P = 0.0117), and the frequency of circulating PD-1 T cells increased with tumor progression (P = 0.0329). By contrast, responders to PD-1/PD-L1 pathway blockade showed a trend of high baseline frequency of intratumoral PD-1 CD8 T cells. Moreover, we observed a trend of LAG3 and TIM3 upregulation on circulating T cells in nonresponding patients to PD-1/PD-L1 pathway blockade. DISCUSSION: Immunosuppressive state, characterized by an enhanced intratumoral CD4/CD8 T-cell ratio, was associated with poor prognosis. Additionally, our results suggest that the frequency of intratumoral PD-1 CD8 T cells may serve as a biomarker to identify which individuals will benefit from which treatment and support the use of combination strategies.

The PPARδ agonist GW0742 restores neuroimmune function by regulating Tim-3 and Th17/Treg-related signaling in the BTBR autistic mouse model.

Autism spectrum disorders (ASD) are neurodevelopmental disorders that are characterized by repetitive behaviors, and impairments in communication and social interaction. Studies have shown that activation of peroxisome proliferator-activated receptor-delta (PPARδ) causes anti-inflammatory effects in animal models of neuroinflammatory diseases. We investigated the possible anti-inflammatory effect of a PPARδ agonist, GW0742 in the BTBR T+ Itpr3tf/J (BTBR) mouse model of autism. BTBR and C57BL/6 (B6) mice were treated orally with GW0742 (30 mg/kg, p.o., once daily) for 7 days. Effect of GW0742 treatment on repetitive behavior, marble burying, and thermal sensitivity response was assessed on day 8. We further examined the effect of GW0742 treatment on immunological parameters in splenocytes using flow cytometry (CD4+TIM-3+, IL-17A+TIM-3+, IL-17A+CD4+, RORγT+TIM-3+, RORγT+CD4+, Stat3+TIM-3+, Foxp3+TIM-3+, Foxp3+CD4+, and IFN-γ+CD4+). We also explored the effects of GW0742 on mRNA and protein expression of TIM-3, IL-17A, RORγT, Stat3, IFN-γ, Foxp3, and IL-10 in the brain tissue using RT-PCR and western blot analyses. GW0742 treatment substantially decreased repetitive behaviors, and lowered thermal sensitivity response in BTBR mice. GW0742 attenuated the expression of inflammatory markers such as IL-17A, RORγT, Stat3, TIM-3, and IFN-γ, while upregulating anti-inflammatory markers such as IL-10/Foxp3 both in the brain and periphery of BTBR mice. In conclusion, this study suggests that GW0742 corrects neurobehavioral dysfunction in BTBR mice which is concurrent with modulation of multiple signaling pathways.

TNFα blockade overcomes resistance to anti-PD-1 in experimental melanoma.

Antibodies against programmed cell death-1 (PD-1) have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-tumor necrosis factor α (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNF signalling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TILs) in mouse melanoma. Herein, our results indicate that TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune responses towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens. This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients.

The Potential Role of Inhibitory Receptors in the Treatment of Psoriasis.

Psoriasis is a common autoimmune disorder that affects the skin. Approximately 30% of individuals with psoriasis will develop inflammatory arthritis, often in the setting of human leukocyte antigen B27. Both forms of disease are thought to be the result of prolonged inflammation mediated by T lymphocytes, dendritic cells, and keratinocytes. While there are treatments aimed at immunomodulation, targeting T cell co-inhibitory receptors signaling pathways may provide therapeutic benefit. This review will discuss in detail four T cell co-inhibitory receptors and their potential application for the treatment of psoriasis and psoriatic arthritis.