Beyond PD-1: novel checkpoint receptors and ligands as targets for immunotherapy

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 hemostasis under physiological conditions, dysregulation in the tumor microenvironment perturbs the role of these molecules with the promotion of exhausted cytotoxic cells, that is cytotoxic cells that no longer are able to control tumors. ICI leverages these targets to redirect cytotoxic responses and neutralize the suppressive tumor microenvironment. However, not all tumor types or patients respond to these therapies. Great interest continues to be focussed on first-generation ICI therapy (PD-1/PD-L1 and CTLA-4) but the potential for other targets and ligands remains vast.

To move beyond these original targets one must focus on emerging immunosuppressive molecules in exhausted cells, such as TIGIT, Tim-3, LAG-3, VISTA, BTLA, CD161, GITR, NKG2A, A2AR, the yet unknown receptors of B7H3, B7H4, and the enzymes IDO1, CD39, CD73, and CD38. These receptors, and/or their ligands may be considered targets in combination with traditional ICI, as stand-alone objectives, or as biomarkers to select patient populations most likely to respond to ICI therapy. The flip side of the coin is receptors that selectively activate cytotoxic cells, such as OX40, 4-1BB, GITR, ICOS, NKG2D, CD6, CD2, CD70/CD27, IL2R, NKp46, CD16, CD40, TLR3/9, and their agonists is relatively unexplored in comparison with the inhibitory checkpoint pathways. Just as inhibition of an inhibitory pathway has shown incredible promise in re-invigorating exhausted cells, the addition of agonistic activating signals via the above receptors shows great potential for reactivation of anti-tumor immune responses.

Putting these two ideas together, that is that both next-generation inhibitory targets and underutilized co-stimulatory activating receptors may be present on the aforementioned exhausted cells, opens the door to novel designs for multi-specific redirectors or functionalized CAR-T or NK cells.

Recently the role of MSI as a selective marker in combination with PD-1 blockade has been made very evident. This leads to the question: what else “upstream” might control the expression of biomarkers such as PD-L1? Of a tumor turning from “cold” to “hot?” What role do molecules such as TOX have in controlling the expression of traditional ICI targets such as PD-1 and CTLA-4?

With thousands of clinical trials focused on the classical checkpoint targets currently in play, the fact remains that this very promising technology does not work for all cancers, nor all patients within a given cancer classification. Here, we would like to present articles to readers seeking new checkpoint targets, novel technologies utilizing checkpoints, or biomarkers that can optimize patient selection for future studies.

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 in the tumor microenvironment and/or cancer cells.
2. Identification of novel checkpoint interactions between cancer and immune cells.
3. Use of agonists of co-stimulatory checkpoint receptors to selectively activate cytotoxic cell populations.
4. Identification of anti-tumor checkpoint targets on innate cells, such as NK, NKT, ILC, and MAIT cells.
5. Combination of ICI with targeted cancer treatments or emerging technologies to synergize therapeutic results.
6. Application of multiple checkpoint targets to improve selectivity and specificity in re-directing T cells or in CAR strategies
7. Identification of unique biomarkers or biomarker combinations to predict response to checkpoint blockade.

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.


Posted on

January 30, 2020