Not all cancers respond strongly—or at all—to immunotherapies. The more responsive cancers include “hot” tumors, which have many intratumoral T cells, whereas the less responsive cancers, such as prostate cancer, include “cold” tumors, which have few intratumoral T cells, such that the immune response is weakened. Cold tumors keep their cool, in part, by hiding from the immune system.
To turn up the heat on cold tumors, scientists based at the University of Michigan Health Rogel Cancer Center chose to rekindle interest in ubiquitin-like modifier activating enzyme 1, or UBA1. It had previously been established as an essential presence in cancer cells, one that could be targeted to achieve antitumor effects directly. Indeed, UBA1 was targeted with inhibitor drugs such as TAK-243 with some success. However, no testing had been done to determine what, if any, effects UBA1 inhibition could have on the tumor microenvironment or the overall immune response.
In a new study, the University of Michigan team, led by Arul M. Chinnaiyan, MD, PhD, has identified the UBA1 enzyme as a key mediator for the immune response to a tumor. The team demonstrated that inhibiting UBA1 increases T-cell recruitment and lowers tumor resistance to immunotherapies.
Detailed findings recently appeared in Cancer Discovery, in an article titled “The UBA1-STUB1 axis mediates cancer immune escape and resistance to checkpoint blockade.”
“By screening candidate genes frequently gained in cancer, we identified expression of ubiquitin-like UBA1 as being the most negatively correlated with signatures related to effector CD8+ T-cells,” the article’s authors wrote. “High UBA1 expression was strongly predictive of treatment resistance and poor survival in ICB cohorts.”
“Functional studies revealed that UBA1 mediated immune escape to promote tumor growth. Immune profiling further showed that Uba1 overexpression or depletion markedly decreased or increased functional intratumoral CD8+ T-cells, respectively.”
The researchers analyzed genetic data from 208 metastatic prostate tumor samples, looking at more than 600 genes and their correlation with interferon-gamma (IFNG). They found 17 genes that negatively correlated with IFNG expression, indicating a dampened immune response to the cancer’s presence.
Among those, UBA1 had the strongest negative correlation with IFNG expression. Patients whose tumors had high levels of UBA1 expression also tended to be more resistant to immune checkpoint blockade (ICB) therapy, leading to poorer outcomes.
To explore whether the negative correlation between UBA1 and IFNG was causal, the researchers then carried out preclinical studies in which they over- or underexpressed UBA1 in tumors in mice. Mice with higher expression levels of UBA1 had faster-growing tumors, while those with lower UBA1 expression had slower-growing tumors.
The researchers found that UBA1 overexpression was blocking CD8+ T cells from being recruited to the tumor, allowing the tumor to escape immune surveillance and rapidly grow.
“Importantly, a selective UBA1 inhibitor, TAK-243, significantly synergized with ICB in multiple syngeneic models,” the scientists explained. “Mechanistically, depletion or inactivation of the UBA1-STUB1 axis stabilized a key interferon pathway component (JAK1), enhanced IFN-signaling, and elevated key immune modulators, including CXCL9, CXCL10, and MHC class I.”
With a mechanism now in hand, the researchers tested whether using TAK-243 to inhibit UBA1 would increase CD8+ recruitment in immunocompetent mice. And it did: half of the mice treated with TAK-243 and an ICB therapy had their tumors disappear.
“It’s exciting to have established this link between UBA1 and T-cell recruitment,” Chinnaiyan said. “This hasn’t really been described before. And that this could impact the immune system so profoundly is surprising [and really opens the doors to potential new therapy combinations].”
The findings mean that pairing TAK-243 with immune checkpoint blockade therapies could make immunotherapy far more effective, or even open the door to use for patients with cold tumors.
“We’ve laid the groundwork that this combination of UBA1 inhibitors and ICB could work well in certain cancer types,” Chinnaiyan declared. “There’s still more research to be done into the mechanisms behind this, but it’s exciting to think that this work might stimulate companies to develop more UBA1 inhibitors. But with TAK-243 already available, this therapy combination might not actually be so distant.”
