*For medical professionals only
I believe that many people's concept of "cancer immunotherapy" began with the PD-1/PD-L1 pair of immune checkpoint proteins.
The importance of PD-1/PD-L1 targets is self-evident, but it is obviously impossible to rely on PD-1/PD-L1 to eat all over the world, and there are still a considerable number of patients who show resistance or limited response to it, and have to find another way.
Recently, Xu Jie's team from Shanghai Medical College of Fudan University published the latest research results in the top international journal "Cell" [1], bringing new enlightenment to the field of cancer immunotherapy.
They found a new immune checkpoint protein, ITPRIPL1.
ITPRIPL1 is abnormally expressed in various tumor tissues, and the ITPRIPL1 on tumor cells binds to CD3ε molecules on T cells, which can inhibit T cell activity. Based on this mechanism, the research team developed antibodies that target ITPRIPL1 inhibition, block the interaction between ITPRIPL1 and CD3ε, and lift the brakes on T cells, so that T cells can effectively destroy tumor cells and significantly inhibit tumor growth in mice and dogs.
Screenshot of the first page of the paper
ITPRIPL1 is a functionally uncharacterized transmembrane protein that is normally predominantly enriched in the testis and widely overexpressed in a variety of human cancer types.
In this study, Jie Xu's team used the Encyclopedia of Cancer Cell Line (CCLE) dataset to screen and found that the expression of ITPRIPL1 and PD-L1 in tumor cells showed a mutually exclusive pattern. In line with this result, transcriptome data analysis of cancer patients showed that the expression of ITPRIPL1 was significantly increased in tumor tissue samples that did not respond to PD-1 inhibitor treatment.
ITPRIPL1 and PD-L1 are mutually exclusively expressed in tumor cells
This means that ITPRIPL1 may also be a trick for tumor immune evasion, independent of the PD-1/PD-L1 pathway.
As a result, the research team further verified the identity of the ITPRIPL1. The results suggest that ITPRIPL1 is an inhibitory ligand for CD3ε expressed by T cells.
CD3ε, who is it?
The T cell receptor (TCR)-CD3 complex on the surface of T cells plays a central role in the initiation of T cell responses. The eight subunits make up the TCR-CD3 complex, each with different responsibilities: recognizing and binding tumor-specific antigens presented by major histocompatibility complex (MHC) molecules to track tumor cells, or relaying the received signals to T cells to initiate a series of intracellular cascades that activate T cells for proliferation, differentiation, and secretion of multiple cytokines. CD3ε belongs to the latter group and is responsible for regulating T cell activity.
Previous research has focused on how MHC-peptides can be used to deactivate TCR-CD3 complexes, such as immunotherapies such as cancer vaccines and TCR-T cell therapy. However, the presence of natural inhibitory ligands in the TCR-CD3 complex has rarely been reported......
Won't we find it this time!
Xu Jie's team revealed that ITPRIPL1, as an immune checkpoint protein, can bind to and interact with the CD3ε subunit on the surface of T cells, resulting in the inhibition of phosphorylation of key kinases ZAP70 and ERK in TCR-CD3 complex signaling, weakening T cell responses, reducing T cell cytotoxicity and proliferation, and reducing cell membrane calcium influx.
mechanism
This means that TCR-CD3 complex activity is regulated by at least two signals: one mediated by the interaction of MHC with TCR, which represents "on", and the other by the interaction between ITPRIPL1 and CD3ε, which represents "off".
Based on the ITPRIPL1/CD3ε pathway, the research team developed a neutralizing antibody 13B7A6H3 (abbreviated as 13B7).
In vitro experiments, this antibody exhibited high affinity and specificity for human ITPRIPL1 proteins, and could potently block the interaction of ITPRIPL1 with CD3ε. And considering that in addition to tumor tissue, ITPRIPL1 is also specifically expressed in healthy testes, the research team explored the potential effects of antibody drugs on other organs. Anti-ITPRIPL1 antibody treatment at a dose of 5 mg/kg on wild-type mice showed that no significant changes were observed in organs such as the heart, kidneys, lungs, and liver, showing a favorable safety profile.
Experimental results in mouse models of melanoma, colorectal cancer, mast cell carcinoma and other tumors, as well as humanized mice closer to the human immune microenvironment, showed that anti-ITPRIPL1 antibody therapy can significantly reduce tumor volume, inhibit tumor growth, improve tumor immune environment, and increase tumor infiltrating CD8+ T cell levels in a dose-dependent manner.
In addition, the research team also treated 6 dogs with spontaneous tumors with anti-ITPRIPL1 antibodies, and almost all of the dogs showed clinical benefit, with tumor growth retardation after treatment.
Anti-ITPRIPL1 antibody treatment for cancer-stricken dogs
For us humans, the research team found that ITPRIPL1 is overexpressed in a variety of solid cancers, including non-small cell lung cancer, breast cancer, rectal cancer, and thyroid cancer, compared to normal tissues. In addition, the expression level of ITPRIPL1 was positively correlated with the stage of tumor progression, and negatively correlated with the level of CD8+ T cells infiltrated by tumors. These results demonstrate the clinical translational value of ITPRIPL1 treatment.
Expression of ITPRIPL1 in cancer patients
All in all, this study reveals a new immune checkpoint protein ITPRIPL1 and finds a "brake" for the TCR-CD3 complex. ITPRIPL1 on tumor cells are mutually exclusively expressed with PD-L1 and regulate T cell activity through mechanisms independent of the PD-1/L1 pathway. Anti-ITPRIPL1 antibodies are able to reactivate T cells in tumors, enhancing their ability to attack tumors, thereby overcoming tumor resistance to existing immune checkpoint blockade therapies.
Who else is hindering the anti-tumor function of T cells, dig it all out!
Bibliography:
[1]https://www.cell.com/cell/abstract/S0092-8674(24)00310-6
The author of this article丨Zhang Aidi