Variants in the APOE gene are the strongest genetic risk factor for developing Alzheimer’s disease (AD).

Now, researchers at Rockefeller University have demonstrated that APOE variants also affected the risk of progression and metastasis as well as the response to immunotherapy, in melanoma. The team published its findings in the May 25, 2020, online issue of Nature Medicine.

The APOE4 allele, which increases the risk of AD, improved the outlook for melanoma patients – possibly by the same biological effect.

“ApoE2, which reduces AD risk, is less effective at enhancing immunity,” senior author Sohail Tavazoie told BioWorld, because it binds less strongly to ApoE receptors.

The greater inflammation caused by ApoE4 is good for a melanoma patient, where “you want a robust inflammatory response” to set off antitumor immunity, he added. “But for your brain, you don’t want inflammation.”

The same link to inflammation may be behind a recent report that the APOE4 variant is linked to worse outcomes in COVID-19 patients.

For melanoma, Tavazoie, who is Leon Hess professor of cancer biology at the Rockefeller University, pointed out that unlike germline variants in BRCA and other cancer risk genes, “we don’t find that [ApoE variants] impact whether you’re going to get melanoma. They impact the future trajectory of it… Your hereditary genetics can be instructive of your risk of relapse.”

In previous studies, Tavazoie and his colleagues discovered that the ApoE protein could suppress cancer progression and metastasis.

Further experiments linked LXR activation to innate immune activation.

Given the famously extreme difference between ApoE variants in AD – individuals with two APOE4 alleles have a 12 to 14 times higher risk of developing AD than those with two APOE2 alleles – “[first author] Ben Ostendorf… and I started to think about genetics” in the context of cancer, as well, Tavazoie said.

To test whether APOE variants affected melanoma, the team used genetically altered mice with human APOE. They showed that both tumor progression and metastasis formation were slower in APOE4 mice, and that such mice had stronger responses to PD-1 checkpoint blockade.

In a retrospective study of two separate melanoma patient cohorts, APOE4 carriers had a longer median survival than APOE2 carriers. And in the clinic, too, patients with APOE4 benefited more from checkpoint blockade than those with APOE2.

Those results suggest that APOE status could be both a prognostic biomarker for melanoma – and possibly other tumor types – and a predictive biomarker for immunotherapies.

Given that 25% of the population have at least one copy of APOE4, and 60% have at least one copy of APOE3, the helpful variants are clearly no guarantee of immunotherapy success.

Response rates remain below 50% even in the tumor types that are most likely to respond to immunotherapy, and within the single digits in some less responsive cancers.

Nevertheless, the findings may help stratify patients both with respect to immunotherapy, and with respect to identifying those patients most at risk of relapse, where more aggressive treatment might be warranted.

Tavazoie is a co-founder, with two of his siblings, of Rgenix Inc. The company is in clinical trials with the liver X receptor (LXR) agonist RGX-104.

LXR controls ApoE production, and the work now published in Nature Medicine suggests that RGX-104 will be more effective in patients with ApoE4 and ApoE3 variants.

Scientifically, the work opens up the possibility that germline variants of other genes may affect tumor progression and/or responses to treatment.

Tavazoie said he is “very excited” about looking for other such genes, using the same method his team used to identify ApoE – first identifying genes that play a role in tumor progression, and then testing the effects of different variants of those genes.

“As an oncologist and cancer biologist, I always thought that you get a tumor, and then you have good luck or bad luck depending on how the tumor evolves,” he said. But his team’s findings are “a remarkable testament to our hereditary genetics” in cancer progression.

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