Targeted inhibition of a 'signal jammer' protein may improve tumor response to immunotherapy

Targeted inhibition of a "signal jammer" protein may improve how tumors respond to immunotherapy. Published today in Nature, a new study demonstrates how some cancer cells use the protein voltage-dependent anion channel 2 (VDAC2) like a signal jammer to prevent the body's anticancer systems from communicating with the immune system. The research also reveals the unexpected central role that mitochondria, cellular organelles involved in energy production, play in this anticancer and immune communication. This proof-of-principle from St. Jude Children's Research Hospital may guide future immunotherapy for cancers that have so far been largely resistant to such treatments, including pediatric solid tumors. 

Successful solid tumors find ways to bypass or hide from the immune system, limiting immunotherapies' effects. In a healthy individual, T cells find cancer cells and release the protein interferon-gamma, a potent cytokine that stops tumor growth. However, interferon-gamma has limited effects on directly killing tumors in many cancers, which impedes anticancer therapies. The St. Jude scientists showed that VDAC2 to overcome these effects of interferon-gamma. Removing VDAC2 in the presence of interferon-gamma increased cancer cell death directly and made tumors more inflammatory, thereby making tumors more vulnerable to different kinds of immunotherapy. These findings provide evidence for future therapeutic development for inhibitors of proteins like VDAC2 that have dual protective roles for impeding tumor cell death and inflammatory rewiring of cancer cells. 

Despite the curative potential of immunotherapy, many patients still don't respond to it. We discovered a very potent way to enable cancers to be more responsive to T cells and immunotherapy by targeting proteins with dual protective roles in the tumor." 

Hongbo Chi, PhD, corresponding author, St. Jude Department of Immunology

To identify the proteins most responsible for helping tumors resist immunotherapy, the researchers used CRISPR-Cas9 screens to target metabolism-related genes in cancer cells. They then exposed those modified cancer cells to interferon-gamma or T-cell treatment to find which genes' absence reduced tumor growth or promoted their killing. Through these screens, removing VDAC2 from tumors had a profound effect, drastically increasing sensitivity to immunotherapies in previously resistant mouse models of skin, colon and liver cancers. 

VDAC2 'jams' calls in and out of tumors 

With those initial results, the researchers investigated how VDAC2 protects resistant tumors. They showed that VDAC2 can act like a cell phone jammer. It prevents tumor cells from receiving calls from and sending calls to the immune system. However, when the scientists removed VDAC2, tumor cells better received the calls from interferon-gamma produced by T cells, causing the tumor cells to activate cell death pathways. These received calls also enabled tumor cells to activate fast-acting "innate" signaling pathways. Specifically, targeting VDAC2 caused tumor cells to release inflammatory molecules called type I interferons, which sent out calls from the tumor cells to the adaptive immune system, much like how the innate immune system mediates early immune responses to infections. 

"Normally, type I interferons are produced as part of the early innate immune system and act before the adaptive immune cells, such as T cells, arrive," said co-first author Renqiang Sun, PhD, St. Jude Department of Immunology. "We were excited and surprised to find that this process can work in reverse, as T cells, via interferon-gamma, led to an increase in innate-like immune activation in cancer cells that then led to more anticancer effects. These observations may help us find novel ways to improve immunotherapy." 

An unexpected role for mitochondria, the 'powerhouse of the cell' 

Unexpectedly, the jammed signal within cancer cells was coming from mitochondria, which has its own unique DNA. As cellular powerhouses, mitochondria coordinate growth and death signals related to energy production. When cancer cells lacked VDAC2, interferon-gamma could break open mitochondria, causing them to release their unique DNA and trigger type I interferon production. That mitochondrial DNA activated special DNA sensors, cGAS–STING signaling. The mitochondria also released the molecule cytochrome c, which activates cell death pathways directly, causing some tumor cells to self-destruct. 

"We showed mitochondria are much more important in antitumor immunity than previously thought," said co-first author Sujing Yuan, PhD, St. Jude Department of Immunology. "This opens up new avenues for researchers to modify mitochondrial function in tumors to make them more vulnerable to immunotherapies and other treatments." 

No drugs currently exist to inhibit VDAC2 specifically. However, the study provides insight that could lead to inhibitors of VDAC2 or parts of its signaling pathway. It also serves as a proof-of-principle for targeting these signal jammer proteins. 

"We've uncovered a new theme in potential drug targets within tumors," Chi said. "Targeting signaling molecules that protect tumor cells in multiple ways, such as preventing inflammation and cell death in the case of VDAC2, is an exciting direction to explore for therapeutic intervention by making tumors more responsive to T cells and enhancing immunotherapy efficacy."