▎ WuXi AppTec content team editor
In cancer treatment, emerging immunotherapy has the effect of killing tumor cells by reactivating the patient's immune system. Among them, a more common class of drugs is immune checkpoint inhibitors, including anti-PD-1 antibodies. Such drugs have achieved optimistic results in some cancer patients, but the overall response rate is still limited. In order to benefit more patients, clinicians and researchers use different therapies to better improve the efficiency of immune checkpoint inhibitors in killing tumors.
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Clinical trials are currently examining the effects of a retinoic acid-associated orphan receptor γt (RORγt) agonist in combination with an anti-PD-1 antibody. Recently, a research team led by Researcher Zhu Di of Fudan University published a paper in the journal Journal of Experimental & Clinical Cancer Research in the field of oncology, demonstrating that RORγt agonists can improve the efficacy of immune checkpoint inhibitors and reveal the pharmacological mechanism of action of drug combination. This result provides a theoretical basis for the screening of patients in clinical trials and provides new ideas for the clinical treatment of tumor immunology.
RORγt is specifically expressed in immune cells and is a major transcription factor in Type 17 T cells. Such cells include Th17 and Tc17, the auxiliary CD4+ T cell subtype and the killer CD8+ T cell subtype that produce the cytokine IL-17, respectively, and play an important role in the progression of autoimmune diseases and the body's defense process. Previous studies have found that RORγt can promote type 17 T cell differentiation, regulate T cell survival, drive T cell activation, and secretion of effectors such as IL-17, and is considered a drug target for anti-cancer and anti-inflammatory disease.
This time, the research team designed an effective, selective small molecule RORγt agonist (8-074), which showed strong anti-tumor efficacy in mice transplanted with tumor cells and improved the efficacy of anti-PD-1 in mouse lung cancer models.
Experimental analysis showed that RORγt agonists played a role in regulating the tumor immune microenvironment by promoting tumor infiltration of CD8+ T cells. Specifically, by improving the function of Type17 T cells, RORγt agonists increased the migration of dendritic cells (MoDCs) derived from monocytes, and the chemokine CXCL10 released by MoDC increased, which attracted CD8+ T cells. In addition, RORγt agonists also promote Type 17 T cell migration and tumor infiltration by upregulating the expression of CCL20 and CCR6.
▲Schematic diagram of the mechanism of RORγt agonist in regulating the tumor immune microenvironment revealed in this study (Source: Reference[1])
It is worth mentioning that the research team also found in previous work that RORγt agonists can improve the immune microenvironment by reducing the proportion of immunosuppressive cells Treg, and can effectively inhibit tumor growth in multiple cancer models with different response rates to immune checkpoint inhibitors.
Taken together, these results show that the two mutually supportive mechanisms cause cascading amplified immune infiltration effects, improve the tumor immune microenvironment, and provide favorable conditions for immune checkpoint inhibitor therapy response. Researcher Zhu Di concluded: "Our series of studies shows how the Th17 cell transcription factor RORγt enhances the anti-tumor immune effect of PD-1 in the tumor microenvironment, providing new insights into the mechanism of action of RORγt agonists in immunotherapy." ”
Resources:
[2] Tian et al (2021), RORγt agonist synergizes with CTLA-4 antibody to inhibit tumor growth through inhibition of Treg cells via TGF-β signaling in cancer. Pharmacological Research Doi: https://doi.org/10.1016/j.phrs.2021.105793
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