New mechanism in a single gene found to supercharge the immune system against various cancers

Good news! Cancer is history (soon)!

"... the research uncovered that less active versions of a gene called NOD2, in combination with radiotherapy or immunotherapy, may help supercharge the immune system’s ability to attack cancer.

The discovery could pave the way for more personalised and effective immunotherapy treatments against a range of cancers. ...

To understand why some people respond well to anti-PD1 and others don’t, ...  researchers studied a group of people who responded exceptionally well to this therapy.

From a group of 742 Australians with the most common form of advanced lung cancer who underwent treatment with anti-PD1, the team identified 40 whose immune system responded very well, as seen by longer survival accompanied by autoimmune reactions. When the researchers analysed their inherited genes, they found that they were more than twice as likely as the general population to have less active versions of a gene called NOD2, in combination with an autoimmune type reaction caused by the immunotherapy.

“This suggests that blocking two different mechanisms, one governed by PD-1 and the other by NOD2, combines to supercharge the immune system against cancer cells. This was a surprising finding ...

Encouragingly, the immune-boosting effect of NOD2 was not limited to lung cancer. The team showed that in 160 people with a range of cancers who had undergone anti PD-1 treatment, those who had less active versions of NOD2 showed a better response to the therapy. Furthermore, the role of the NOD2 pathway in immunotherapy response was confirmed in preclinical models of colorectal cancer. ..."

From the significance and abstract:

"Significance

These results help to explain, in part, the large variability in clinical response to a widely used cancer immunotherapy by revealing an inherited contribution from common functional variants in a single gene, NOD2. The results show that NOD2 is an important immune checkpoint not only for tolerating the gut microbiome but for human immune tolerance against cancer cells. The findings raise the possibility that NOD2 genotyping may be useful as a predictive biomarker for anti-PD1 monotherapy of cancer, and that pharmacological inhibition of NOD2 signaling might improve therapeutic anticancer immunity.

Abstract

Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients.

Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes.

Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, NOD2, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma.

In 40 exceptional immune responders to anti-PD1 monotherapy for non–small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a NOD2 LOF variant, more than twice the population frequency (P = 0.0021).

Conversely, a gain-of-function RIPK2 allele known to increase NOD2 signaling was inherited by 61% of nonresponders from the same cohort, compared to 10% of exceptional responders and much higher than the population frequency (P < 0.0001).

Within the overall recruited cohort of 144 NSCLC anti-PD1 patients, individuals with immune-related adverse events (irAE) had better overall survival, further improved in those with NOD2 LOF.

In independent anti-PD1 monotherapy cohorts with a range of cancers, inherited NOD2 LOF was associated with complete or partial response (P = 0.0107). Experimental validation in mice showed germline Nod2 LOF enhanced therapeutic immune responses elicited by anti-PD1 monotherapy against a high mutation burden colorectal cancer, increasing tumor infiltration by effector memory CD8 T cells.

Collectively these results reveal common inherited human variation in an immune tolerance checkpoint is a determinant of cancer immune responses elicited by pharmacological inhibition of another checkpoint."

New mechanism found to supercharge the immune system against cancers | Garvan Institute of Medical Research "Garvan researchers have discovered new pathways that may explain differences in the way people with cancer respond to immunotherapy"

Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy (open access)