Two independent research teams have discovered the same previously overlooked immune checkpoint that may help explain why some cancers resist immunotherapy.
In a study published today in Nature, researchers at Erasmus University Medical Center (Erasmus MC) identified phospholipase A2 group IID (PLA2G2D) in the tumor-draining lymph nodes (TDLNs) of patients with melanoma. The team found that the molecule acts as an immune checkpoint, essentially putting the brakes on the proliferation of tumor-reactive T cells before they reach the tumor.
Separately, Apeximmune Therapeutics identified PLA2G2D through a computational analysis of more than 9,000 primary tumor samples. In a press release, the company said its analysis ranked PLA2G2D above established immune checkpoints PD-1 (programmed death 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4).
Together, these findings suggest that PLA2G2D represents a distinct immune checkpoint pathway that could be targeted alongside PD-1 to restore antitumor immunity in patients who do not respond to checkpoint inhibitors.
Before T cells reach the tumor
Immune checkpoint inhibitors such as anti-PD-1 antibodies have transformed cancer treatment by releasing the molecular brakes on T cells, allowing them to mount a stronger response against tumors. But the majority of patients across indications either fail to respond or eventually relapse.
Much of the research into this resistance has focused on the tumor microenvironment (TME), where cancer cells and surrounding immune cells can suppress T cell activity. The new study instead points to an earlier stage of the immune response in the TDLN.
TDLNs serve as critical sites where tumor antigens are presented to immune cells, helping to prime and expand tumor-reactive T cells before they migrate into the tumor. The Erasmus MC team therefore set out to understand whether immune suppression in these lymph nodes could influence the body’s broader antitumor immune response.
Using spatial proteogenomics on melanoma TDLNs from patients with different outcomes, the researchers found that myeloid cells expressing PLA2G2D were more prevalent in the lymph nodes of patients with worse outcomes.
“We were asking a straightforward question: how do cancer cells block effective anti-tumor immune responses where they are first generated, in the lymph node?” Floris Dammeijer, a researcher at Erasmus MC and coauthor of the study, said in the press release. “The answer, unexpectedly, kept pointing to PLA2G2D.”
The researchers found that PLA2G2D functions as a lymph node-centered immune checkpoint, suppressing the proliferation of antitumor T cells. Removing PLA2G2D, either genetically or with an antibody, was shown to inhibit tumor growth in preclinical models.
The effects were even more apparent when PLA2G2D blockade was combined with anti-PD-1 treatment, suggesting that PLA2G2D and PD-1 may regulate distinct parts of the immune response. In preclinical models, PLA2G2D blockade also restored antitumor immunity in tumors resistant to anti-PD-1 therapy and enhanced anti-PD-1 activity in tumors that otherwise failed to respond to checkpoint inhibition.
This suggests that PLA2G2D blockade could help overcome resistance to anti-PD-1 therapy and extend checkpoint inhibition to tumors that have historically been difficult to treat.
An enzyme with another role
Apeximmune's research also uncovered a mechanism that previous investigators may have overlooked. PLA2G2D has long been characterized for its phospholipase activity, and previous efforts to drug the broader sPLA2 family have focused on its enzymatic function. The company found that an enzyme-dead version of PLA2G2D retained potent immunosuppressive activity, indicating that the molecule can suppress immune responses independently of its phospholipase activity.
That distinction could be important for drug development. Rather than simply inhibiting the enzyme's catalytic function, Apeximmune designed an antibody intended to block both the enzymatic and nonenzymatic activities of PLA2G2D.
“This independent identification of the same target by the Erasmus team, using entirely different methods and starting from patient samples rather than computational discovery, is the strongest possible validation of the underlying biology,” said Li-Fen Lee, founder and CEO of Apeximmune, in the press release.
Discovering that a team at Apeximmune had independently reached the same target, from an entirely different starting point, was extraordinary.
—Ralph Stadhouders, Erasmus MC
Ralph Stadhouders, a researcher at Erasmus MC, said in the press release that the convergence ultimately led the two groups to collaborate. “Discovering that a team at Apeximmune had independently reached the same target, from an entirely different starting point, was extraordinary,” he said. “The collaboration that followed has produced a body of evidence neither group could have generated alone.”
A potential route around PD-1 resistance
Apeximmune is now advancing its lead antibody, AI-306, toward the clinic. The company is currently conducting Investigational New Drug-enabling studies, with cell line development underway and toxicology studies expected to begin in late 2026. The company has also developed PLA2G2D knockout and humanized mouse models to support the program.
If the findings translate clinically, PLA2G2D could provide a new therapeutic route for patients who do not respond to anti-PD-1 therapy and potentially expand the reach of checkpoint inhibition to tumors that have historically been difficult to treat.
