TNF Overcomes Medulloblastoma Immune Evasion

By Will boggs MD

June 04, 2020

NEW YORK (Reuters Health) - Tumor-necrosis factor (TNF) restores expression of surface class I major histocompatibility complex (MHC-I) in p53-mutant medulloblastoma, thereby overcoming its evasion of the immune system, researchers report.

"p53 is a tumor-suppressor gene that is mutated in half of all human cancers, and it has been widely studied as a regulator of cell proliferation, cell death, and responses to DNA damage," said Dr. Robert J. Wechsler-Reya of Sanford Burnham Prebys Medical Discovery Institute, in La Jolla, California.

"But the notion that p53 also controls MHC-I expression and thereby regulates immune responses was quite surprising to us and to our colleagues," he told Reuters Health by email.

Killing of tumor cells by cytotoxic T cells depends on their recognition of antigens presented by MHC-I proteins on tumor surfaces.

Dr. Wechsler-Reya and colleagues found that p53-mutant medulloblastomas are resistant to this T cell-mediated rejection and that inactivation of p53 results in the loss of cell surface MHC-I.

A link between p53 and MHC-I has been described in carcinoma and sarcoma cell lines but not in brain tumors, and its significance for immune evasion has not been investigated in vivo, the researchers note in Nature Neuroscience.

p53 appears to regulate MHC-I localization to cell surfaces by directly regulating expression of Erap1 and Tap1, two proteins required for the intracellular process that trims peptides so they fit properly into the peptide-binding pocket of the MHC-I complex and transporting it to the surface.

Additional experiments showed that TNF and lymphoid toxin-beta receptor agonist could induce expression of Erap1 and Tap1 and thereby restore surface MHC-I expression in p53-mutant tumor cells without altering the expression of p53.

Administration of low doses of TNF to mice implanted with intracranial p53-mutant medulloblastoma cells resulted in upregulation of MHC-I expression by those tumor cells and an increase in the number of T cells within the tumor.

Finally, other mice implanted with p53-mutant tumor cells were treated with vehicle, with the immune-checkpoint inhibitor (ICI) anti-PD-1, with low-dose TNF, or with the combination of anti-PD-1 and TNF.

Median survival was 20 days for mice treated with vehicle only, 25 days for mice treated with anti-PD-1 alone, 32 to 38 days (dose dependently) for mice treated with TNF alone, and 52 days for mice treated with the combination of anti-PD-1 and the lowest dose of TNF (0.1 ug/kg).

"There are two major therapeutic implications of our work," Dr. Wechsler-Reya said. "First, our results suggest that medulloblastomas with p53 mutations lack MHC-I on their surface, and as a result, may be resistant to T cell-based immunotherapy. This may explain why immune-checkpoint inhibitors have not been very successful in these tumors."

"The extent to which this is true for other cancers remains to be determined, but at the very least our results suggest that before enrolling someone on an immunotherapy trial that involves T cell recognition of tumor cells, it might be worth looking to see whether those tumor cells express MHC-I," he said.

"The second major implication is that MHC-I expression can be rescued by exposing tumor cells to low levels of TNF," Dr. Wechsler-Reya said. "Importantly, these are levels of TNF far below those that cause toxicity, in mice or in people."

"The consequences of doing this in our animal models of p53-mutant medulloblastoma are striking," he said. "Left untreated, these tumors grow aggressively in mice. If we treat tumor-bearing animals with the immune-checkpoint inhibitor anti-PD-1, it has little effect, because anti-PD-1 simply affect T cells, and if tumors lack MHC-I they cannot be seen by those T cells. On the other hand, if we treat with TNF first (to induce MHC-I expression), anti-PD-1 has a dramatic effect on tumor growth: the combination therapy completely eradicates tumors."

"Based on these studies, we are developing a clinical trial to test whether TNF can enhance the efficacy of immune checkpoint therapy in children with recurrent medulloblastoma," he said.

Dr. Wechsler-Reya and two of his coauthors are named as inventors on a patent related to the research.

SOURCE: Nature Neuroscience, online May 18, 2020.