Finding new targets on cancer cell surfaces: MPZL1 CAR-T eliminates some tumors in mouse experiments

For immune cells to attack solid tumors, they first need a marker that allows them to recognize cancer cells while avoiding normal tissues as much as possible. A Heidelberg research team focused on MPZL1, a protein found in large quantities on cancer cell surfaces, and designed CAR-T cells targeting it that showed antitumor effects in cell cultures and mouse experiments. The study suggests that, when searching for therapeutic targets, whether a protein is abundantly exposed on the cell surface may be as important as whether it drives cancer.

The study was a collaboration among institutions including Heidelberg University’s Faculty of Medicine, Heidelberg University Hospital, and the German Cancer Research Center. It was published in Nature Communications on September 10, and the hospital announced the findings on October 5. The team first analyzed gene copy number changes in 2,703 cancer samples, then examined MPZL1 protein in 2,335 surgically resected specimens across six cancer types. These represent two distinct levels of analysis; the approximately 2,200 tumor samples summarized in the hospital’s press release were not the only sample count in the study as a whole.

The chromosomal region containing MPZL1 frequently shows increased copy numbers in multiple cancer types, resulting in higher cell surface protein expression in some tumors. The team incorporated an antibody recognition fragment that recognizes human MPZL1 into a chimeric antigen receptor, enabling the modified T cells to launch an attack when they encounter the marker. In the laboratory, these CAR-T cells could kill liver, breast, lung, pancreatic, and glioblastoma cancer cells with high MPZL1 expression. After the MPZL1 gene was knocked out, the corresponding cancer cells could resist this antigen-specific killing, supporting the finding that the attack depends on the target.

A more striking result came from a model in which human liver cancer cells were transplanted into mice: after a single intravenous injection, 7 of 11 tumors with high MPZL1 expression disappeared completely, with no recurrence observed during follow-up through day 60, while the remaining 4 regrew. These counts refer to tumors and cannot be interpreted as a patient remission rate. The researchers also added CAR-T cells to tumor tissue surgically removed from patients and observed cell infiltration and immune activation. By comparison, infiltration and the release of associated signaling molecules were lower in healthy tissue, but these were still ex vivo experiments.

The central safety challenge lies in markers shared by cancer cells and normal cells. The paper notes that MPZL1 expression is lower in most normal tissues, with the uterus and testes as exceptions. These CAR-T cells recognize human MPZL1 but cannot recognize the corresponding mouse protein, so mouse experiments cannot fully assess whether they would attack healthy human tissue. Lower activation in normal tissue provides preliminary evidence, but is not sufficient to establish safety in patients receiving the treatment.

Background Context

Bringing CAR-T therapy to solid tumors requires addressing two challenges at once: target selection and the tumor environment. Some development efforts focus on enabling T cells to resist immune suppression within tumors; the MPZL1 study instead starts with recognition, seeking to use differences in expression levels between tumors and normal tissues. These approaches address different problems, and identifying a recognizable surface protein does not establish that the cells can maintain their activity in humans.

The value of this work also lies in broadening the search for targets: within amplified chromosomal regions, even genes that are not typical cancer drivers may encode surface proteins that immune cells can recognize. Next, researchers need to determine which tumors express enough MPZL1 to support treatment and whether normal organs can tolerate this attack. At this stage, it is a development path supported by experimental evidence; efficacy and safety in patients have yet to be established.