The cover for issue 100 of Oncotarget features Figure 9, "Proposed model for the induction of PD-L1 by Hh signaling," by Chakrabarti, et al.
Tumor cells expressing programmed cell death ligand 1 interact with PD-1 on CD8+ cytotoxic T lymphocytes to inhibit CTL effector function.
Here we tested the hypothesis that Hh-induced PD-L1 inactivates effector T cell function and allows gastric cancer cell proliferation.
Thus, Hh signaling mediates PD-L1 expression in gastric cancer cells and subsequently promotes tumor proliferation.
"The effective diagnosis and treatment of the major gastric cancer risk factor Helicobacter pylori has resulted in the decreased incidence of gastric cancer in the United States."
Figure 9: Proposed model for the induction of PD-L1 by Hh signaling. We proposed from these studies that Hh signaling induces the expression of PD-L1 on gastric tumor cells. When antigen presenting dendritic cells (DC) are pulsed with conditioned media collected from gastric cancer organoids, containing tumor-specific antigen (AN), and co-cultured with CTLs, there is a significant induction of PD-1 on these lymphocytes. Thus, secreted tumor-specific AN induces PD-1 expression on CTLs. The co-culture of CTLs exposed to tumor-specific AN with gastric cancer organoids resulted in the protection of cancer cells from anti-tumor lymphocyte activity. Immune-checkpoint inhibition using anti-PD-1 inhibitor Nivolumab resulted in cancer organoid death.
The effective diagnosis and treatment of the major gastric cancer risk factor Helicobacter pylori has resulted in the decreased incidence of gastric cancer in the United States.
While clinical trials using immune-checkpoint inhibition is proven to be promising for the treatment of gastric cancer, there are no established selection criteria to predict whether a patient will benefit from immunotherapy alone or with combination therapy.
Importantly, the Hh signaling pathway is often overexpressed in various cancers including gastric and pancreatic.
In the current study, we sought to investigate the role of Hh signaling as a mediator of PD-L1 expression during gastric tumorigenesis using an in vivo mouse model of gastric cancer, in vitro mouse-derived gastric cancer organoid/immune cell co-culture, and human-derived gastric cancer organoid drug assays.
"Combinatorial drug treatment of hu TGOs with both Hh inhibitor GANT61 and chemotherapeutic drugs resulted in decreased cancer cell proliferation and induced cell death both in vitro and in vivo.
These data suggest that activation of the Hh signaling pathway renders cancer cells resistant to immunotherapy."
Full text - https://doi.org/10.18632/oncotarget.26473
Correspondence to - Yana Zavros - [email protected]
Keywords - gastric cancer organoids, PD-1, cytotoxic T lymphocytes, dendritic cells
