PLA2G2D in tumour-draining lymph nodes acts as an immune brake

PLA2G2D in tumour-draining lymph nodes appears to act as an immune brake before anti-tumour T cells ever reach the tumour itself. That shifts the usual focus: immune suppression is not confined to the tumour microenvironment. It can also operate in the lymph nodes where T cells are first primed and begin to expand.

A tumour-draining lymph node receives lymph from the region surrounding a tumour. It is one of the places where immune cells encounter tumour antigens and build a systemic response. The study by Anneloes van Krimpen and colleagues suggests that the same site can also contain a distinct mechanism that restrains that response.

A suspicious cellular neighbourhood

The researchers began with tumour-draining lymph nodes from patients with stage II or stage III melanoma whose later clinical outcomes were known. They compared patients who developed an early recurrence with those who remained disease-free for much longer. Using imaging mass cytometry, they analysed 372 tissue regions containing about 870,000 individual cells.

The clearest differences appeared in the paracortex, a T-cell-rich region of the lymph node. In patients who later developed distant recurrence, activated CD8+ T cells were more often found in a particular cellular neighbourhood alongside myeloid cells expressing high levels of PLA2G2D.

PLA2G2D is a secreted protein in the phospholipase A2 family. In this study, it was especially abundant in myeloid cells in tumour-draining lymph nodes, predominantly macrophages. PLA2G2D-positive myeloid cells were much less common in primary tumours and metastases. The association with poor outcome was also supported in independent cohorts of patients with metastatic melanoma and non-small-cell lung cancer.

The human data establish an association, not proof that PLA2G2D causes recurrence. The crucial next question was therefore whether the protein could directly suppress anti-tumour immunity.

The brake acts early

In cultured human T cells, PLA2G2D suppressed proliferation after activation and reduced the production of effector cytokines and granzyme B, a protein cytotoxic T cells use to kill target cells. Gene-expression analysis showed a marked reduction in cell-cycle programmes.

One detail was particularly revealing: the suppressive effect largely persisted when the researchers used a catalytically inactive form of PLA2G2D. The protein therefore seems to restrain T cells largely independently of its conventional enzymatic activity. PLA2G2D bound to the surface of newly activated T cells, but the receptor or molecular target responsible for that interaction remains unidentified.

The mouse experiments moved the evidence from association toward causation. Tumours grew more slowly in mice lacking functional Pla2g2d, and blocking antibodies against PLA2G2D inhibited tumour growth in several experimental cancer models. When CD8+ T cells were depleted, the treatment benefit disappeared, showing that these cells were necessary for the anti-tumour effect.

The timing was equally informative. After PLA2G2D blockade, proliferating tumour-specific CD8+ T cells first increased in tumour-draining lymph nodes and blood, and were subsequently found in greater numbers in tumours. The sequence fits a model in which the immune response is strengthened at its point of initiation rather than only within the tumour.

A checkpoint distinct from PD-1

PLA2G2D does not appear to duplicate the well-known PD-1 checkpoint. The authors therefore tested the two blockades together. In mice engineered to express human PLA2G2D, combining antibodies against PLA2G2D and PD-1 produced additive or synergistic anti-tumour effects depending on the model. The interaction was especially strong in a B16F10 melanoma model that was resistant to PD-1 blockade alone.

This is still preclinical evidence. No patients in the study were treated with anti-PLA2G2D antibodies, so the work does not establish safety or efficacy in humans. The initial deep spatial analysis of human lymph nodes also involved small groups—five or six patients per group—although some findings were subsequently tested in independent cohorts. In addition, the T-cell molecule that receives the suppressive PLA2G2D signal has not yet been identified.

There is also a relevant competing-interest disclosure: several authors are employees of Apeximmune Therapeutics, and therapeutic uses of PLA2G2D antibodies are covered by patents assigned to the company.

The main advance is therefore not a new cancer drug, but a change in where an immune checkpoint can operate. The brake was found not only where T cells confront the tumour, but upstream—in the lymph node where those T cells are being prepared for the fight.