Study cracks the cold case of immunotherapy resistance

Michigan Medicine - University of MichiganDec 3 2024

A study from the University of Michigan Health Rogel Cancer Center may have, at last, cracked the cold case of immunotherapy resistance.

The research, led by Arul M. Chinnaiyan, M.D., Ph.D., identifies the UBA1 enzyme, already known to contribute to tumor growth, as a key mediator for the immune response to a tumor. Inhibiting its activity increases T-cell recruitment and lowers tumor resistance to immunotherapies. 

With at least one UBA1 inhibitor in clinical trials, the findings open the door to a combination immune checkpoint blockade therapy in the not too distant future. The study was published in Cancer Discovery.

We've seen remarkable clinical successes with immunotherapies, especially with this checkpoint therapy."

Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology

Kidney cancers, some melanomas, and non-small cell lung cancers respond well to immune checkpoint blockade.

But not all cancers respond strongly-;or at all-;to immunotherapies. 

Certain cancers considered "cold" tumors, such as prostate cancer, have fewer intratumoral T cells, so the immune response is weaker than for "hot" tumors with many such cells. 

While "hot" tumors typically respond well to immunotherapies, "cold" tumors do not. 

Tumors can also evade immune surveillance, hiding from the immune system and avoiding triggering a swarm of T-cells, and alter the tumor microenvironment. 

As effective as immunotherapies can be, some tumors have gotten "smart," Chinnaiyan said, limiting the therapies' potential.

"One of the challenges has been how to expand the utility of immunotherapeutic approaches to more cancer patients and more cancer types," Chinnaiyan said. 

"With this study, we were looking to identify compounds or approaches that could help us do that."

What blocks an immune response?

Chinnaiyan and his collaborators had their eye on ubiquitin-like modifier activating enzyme 1, or UBA1, which had previously been established as an essential presence in cancer cells. 

While UBA1 had been on investigators' radars, it was primarily as a target with direct tumor cell effects, with inhibitor drugs such as TAK-243 already designed to that end and demonstrated to have anti-tumor efficacy. 

No testing had been done to determine what, if any, effects UBA1 inhibition could have on the tumor microenvironment or the overall immune response.

Chinnaiyan's expertise includes prostate cancer, a strongly cold tumor that has limited responses to immunotherapies, including immune checkpoint blockade. 

The researchers analyzed genetic data from 208 metastatic prostate tumor samples, looking at more than 600 genes and their correlation with interferon-gamma, an anti-tumor gene that immune effector cells produce.

They found 17 genes that negatively correlated with IFNG expression, indicated 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 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 under-expressed 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 to be recruited to the tumor, allowing the tumor to escape immune surveillance and rapidly grow. 

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]."

Expanding immune checkpoint blockade to more cancers-;and more patients

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 said. 

"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, he added, "this therapy combination might not actually be so distant."