Community Series in Beyond PD-1: Novel Checkpoint Receptors and Ligands as Targets for Immunotherapy, Volume II

This Research Topic is the second volume of the “Beyond PD-1: Novel Checkpoint Receptors and Ligands as Targets for Immunotherapy” Community Series. Please see Volume I here

The incredible power of the immune system to control or eliminate neoplasias has been made evident by the success of immune checkpoint inhibitors (ICI). While inhibitory checkpoint receptors are critical for the maintenance of homeostasis under physiological conditions, dysregulation in the tumor microenvironment perturbs the role of these molecules resulting in exhausted cytotoxic cells that express ICIs with subsequent loss of effector function and inability to control tumor growth. Therapies that target ICIs redirect cytotoxic responses and neutralize the suppressive tumor microenvironment. However, not all tumor types or patients respond to well established ICIs. First-generation ICI therapeutics (PD-1/PD-L1 and CTLA-4) continue to receive the most attention, but the potential for other targets and ligands remains vast.

To move beyond first generation ICIs, more focus on second and third generation immunosuppressive molecules in exhausted cells is needed. These include TIGIT, Tim-3, LAG-3, VISTA, BTLA, CD161, GITR, NKG2A, A2AR, the yet unknown receptors of B7H3, B7H4, and others, including highly novel inhibitory receptors.

The flip side of the coin include receptors that selectively activate cytotoxic cells, such as OX40, 4-1BB, GITR, ICOS, NKG2D, CD6, CD2, CD70/CD27NKp46 and others. gAonists targeting stimulatory receptors remain less established as therapeutics in comparison with ICIs. The addition of therapeutics against known and novel agonistic activating signals has great potential for activation of anti-tumor immune responses.

Finally, next-generation therapeutics targeting both inhibitory and stimulatory receptors on dysfunctional T cells in tumors also opens the door to new technologies such as multi-specific redirectors or functionalized CAR-T or NK cells.

In this collection we will present articles to readers seeking new checkpoint targets and novel technologies utilizing checkpoints.

We welcome the submission of Original Research, Review, and Mini-Review articles covering the following topics:

1. Molecular mechanisms underlying the regulation of checkpoint ligand expression and function in the tumor microenvironment.
2. Identification of novel checkpoint and stimulatory pathways between cancer and immune cells.
3. Agonists of co-stimulatory receptors that activate cytotoxic cell populations.
4. Identification of inhibitory targets on innate cells, such as NK, NKT, ILC, and MAIT cells.
5. Combination of novel therapeutics or emerging technologies.
6. Applications to improve selectivity and specificity in re-directing T cells or in CAR strategies.


Manuscripts focusing on PD-1/PD-L1 and CTLA-4 axes are out of scope for this topic. Likewise, manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.