This Research Topic is the second volume of the “TNFRSF Agonists: Mode of Action and Therapeutic Opportunities ” Community Series. Please see Volume I here

The receptors of the TNFRSF (TNFRs) are of overwhelming importance in the regulation of the immune system, cell survival and proliferation, making them excellent therapeutic targets for prominent diseases such as cancer and autoimmunity.

TNFRSF members provide crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFR has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. For example, the two receptors of TNF, TNF receptor-1 (TNFR1) and TNF receptor-2 (TNFR2), regulate the interaction of the various types of immune cells and also the interplay of the latter with practically any type of non-hematopoietic cells; CD40 stimulates antigen-presenting cells; CD27, OX40, 41BB, GITR, HVEM and RANK costimulate T cells; BCMA, TACI, and BaffR regulate B cell maturation; CD95 and the two death receptors of TRAIL contribute to tumor surveillance and Fn14, EDAR and XEDAR have been implicated in tissue regeneration and development. Correspondingly, exploiting TNFR-mediated signaling for the therapy of cancer and non-cancerous diseases is a major field of interest.

A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF receptor into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah.

The goal of this research topic is to provide concise overview of the recent advances in our understanding of agonists targeting TNFRSF and their potential therapeutic use, in particular in cancer and autoimmune diseases. The focus of the series of research and review articles includes but is not limited to the biology of TNFRSF receptors in distinct immune cell populations, structure-function relationship of TNFRSF agonists, current preclinical and clinical knowledge of co-stimulatory TNFR agonists, opportunities for next generation TNFRSF therapeutics alone or in combination with immune checkpoint molecules, including the advances in design of adoptive T cell therapies.

We encourage the submission of original research articles supported by pre-clinical data. Review articles will also be considered. Data should consist of functional activity analyses encompassing various murine or humanized mouse models, assessment of TNFRSF targeting in translational ex vivo primary human tissue settings, or innovative single cell or spatial analysis of TNFRSF expression in patient material and association with disease progression. Submissions should not be limited to the in vitro evaluation of TNFRSF signaling. We expect submissions based on (but not limited to):

• TNFRSF signaling in shaping the immune contexture for anti-tumor immunity.
• Engaging cytotoxic TNFRSF signaling to treat cancer.
• Engaging TNFRSF signaling in non-cancerous diseases.
• Immunobiology of TNFRSF receptors in specific immune cell populations, eg regulatory T cells (TNFR2, 41BB, TNFRSF25, ..), dendritic cells (CD40, RANK …), NK cells …
• Critical aspects of TNFRSF structure-function and receptor clustering .
• Balancing agonistic strength with FcγR affinity in the context of opportunities for next generation anti-TNFR antibodies with improved pharmacologic properties.
• TNFSF-based agonists with conditional or constitutive agonism.
• Potential of simultaneous blockade of immune checkpoint molecules and co-stimulation of the TNFRSF in improving anti-tumor immunity.
• Bispecific TNFR agonists.
• anti-TNF-α agents in cancer immunotherapy.
• Prominence and key features of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) as co-stimulatory domains in CAR-T cell therapy.
• Current preclinical and clinical knowledge of co-stimulatory TNFR antibodies.
• Novel data demonstrating potential of TNFRSF as targets for therapy of autoimmune and inflammatory disease

Dr. Nataša Obermajer is a co-founder and Senior Director of a biotech startup company and listed as an inventor on patent applications for TNFRSF member agonist and bispecific anti-TNFRSF antibodies with conditional activity.
Prof. Dr. Edwin Bremer has no conflict of interests.
The University of Würzburg has filed patent applications for TNFR2, Fn14 and CD40 agonists and bispecific anti-TNFR antibody formats with conditional activity with Dr. Harald Wajant as co-inventor. He is also co-founder of TrimmunoTec GmbH a biotech startup company developing TNFRSF agonists. The University of Würzburg receives funding from Dualyx NV for the development of TNFR2 agonists.

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