Evidence date · 2021-05-07 · Research note 1 of 2
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In mice with implanted glioblastoma, blocking two immune checkpoints—signals that restrain immune activity—was associated with longer survival and changes in the immune cells inside the tumors. The combination targeted PD-1 and TIGIT, two brakes on immune responses. The study also found that the treatment affected one type of immune-suppressing cell in the mouse tumors more clearly than another. These are preclinical findings, not evidence that the combination improves outcomes for people with glioblastoma.
Human tumor data pointed to two related targets
The researchers first examined gene-expression data from 153 human glioblastoma samples. Higher expression of TIGIT and PDCD1, the gene that encodes PD-1, was associated with poorer reported overall and disease-free survival. This association nominated the two pathways for study; it does not show that either one caused worse outcomes or predicts who would respond to treatment.
TIGIT and PDCD1 expression also tracked together, but their associated gene networks were not identical. Some genes and pathways were associated with both, while others were more closely associated with one or the other. That overlap and difference gave the researchers a reason to test a paired approach: the two brakes might restrain immune activity through connected, but not interchangeable, routes.
Two brakes can restrain immune activity in different ways
PD-1 is found on activated immune cells, including T cells that enter tumors. When PD-1 binds PD-L1, a ligand found on tumor and other cells in the tumor environment, it can reduce T cells’ ability to make signaling molecules and kill target cells.
TIGIT is another inhibitory receptor on activated immune cells. It binds CD155, a molecule that can also bind CD226. While CD226 provides an activating signal, TIGIT binds CD155 more strongly, giving the inhibitory interaction an advantage. The pathways therefore converge on restrained immune activity, but their different partners help explain why the researchers tested blocking both.
The mouse comparison linked survival with a stronger T-cell response
The team implanted GL261 glioblastoma cells into mice and compared control antibodies with anti-PD-1, anti-TIGIT, or both antibodies together. Treatment began eight days after tumor implantation and was given in seven doses. The control group had a median survival of 33 days. Median survival was 34 days with anti-TIGIT alone, 37 days with anti-PD-1 alone, and 48 days with the combination. The paper reports that the combination significantly prolonged survival compared with controls. These survival results came from the mouse model.
The researchers assessed tumor immune cells separately, on day 22 after implantation. The combination increased the proportion of CD8 T cells in tumors, and the proportion of CD8 T cells expressing granzyme B—a molecule associated with cell-killing activity—was higher with the combination than with either single treatment. Anti-PD-1 alone also increased the proportion of CD8 T cells, while anti-TIGIT alone did not show that same increase. The findings connect the survival result with a more cytolytic T-cell profile, but they do not establish which immune change was responsible for longer survival.
The suppressive-cell response split by cell type
Tumors also contain myeloid cells, a broad group that includes cells capable of suppressing anti-tumor immune responses. The study distinguished two suppressive myeloid-cell types: granulocytic or polymorphonuclear (PMN) cells, and monocytic cells. In the mouse tumors, the combined treatment reduced the accumulation of PMN suppressor cells. The monocytic subtype did not show the same reported reduction.
This difference adds another part to the proposed mechanism. The combination’s effects were not limited to tumor-infiltrating T cells; they also involved a particular suppressive-cell population. The results suggest that PMN and monocytic cells may not respond alike, though the experiment does not establish why their responses differed.
Human tumor immune cells offered a separate mechanistic link
The researchers also examined human glioblastoma-associated myeloid cells. In their analyses, these cells expressed PD-1, PD-L1, and molecules that bind TIGIT. This shows that relevant checkpoint machinery was present among cells in human tumors, but expression alone does not show that treatment would reverse immune suppression in patients.
In a separate cell-culture experiment, suppressive myeloid cells inhibited the proliferation of antigen-specific T cells. Blocking PD-1 and TIGIT restored that proliferation in the assay. This offers a possible route by which these pathways could restrain T cells, but it is a laboratory result, distinct from treating people or testing clinical benefit.
What paired immune blockade could mean for glioblastoma treatment
A treatment that releases both brakes could, in principle, help tumor-attacking immune cells function while reducing pressure from suppressive myeloid cells. For people with glioblastoma, that would offer a way to address more than one source of immune restraint at once. Whether this capability translates from the mouse mechanism to patients—and whether a regimen can be shown to be safe and beneficial—requires clinical evidence. The study does not establish an effective treatment or a validated marker for selecting patients.
Key Sources
- Primary source: TIGIT and PD-1 Immune Checkpoint Pathways Are Associated With Patient Outcome and Anti-Tumor Immunity in Glioblastoma.
DOI or Journal Page · Clinical Trial · 2021-05-07