NEW YORK – New research suggests that a subset of metastatic uveal melanoma cases contains transcriptomic markers for immune cell features that predict their response to adoptive tumor infiltrating lymphocyte (TIL) therapy.
"We demonstrate that adoptive transfer of these transcriptomic-selected TIL can promote tumor immunity in patients with metastatic [uveal melanoma] when other immunotherapies are incapable," senior and corresponding author Udai Kammula, a researcher with the University of Pittsburgh's UPMC Hillman Cancer Center and director of the UPMC Hillman Cancer Center's solid tumor cell therapy program, wrote with his colleagues in a paper appearing in Nature Communications on Tuesday.
For their analyses, the researchers relied on 10x Genomics-based RNA sequencing to profile transcriptomic, genomic, and immune cell patterns in 100 uveal melanoma metastasis samples from 84 patients.
Unlike cutaneous melanoma, where immune checkpoint blockade immunotherapy is often beneficial, they explained, uveal melanoma has remained largely resistant to such treatments, consistent with the view that such tumors are immunologically "cold."
Even so, the team's multiomic analyses suggested T-cell infiltration does occur in a significant subset of uveal melanoma metastases, with tumor-reactive TILs turning up in 55 percent of the metastatic tumors.
"Our findings establish that metastatic [uveal melanoma] is not an immunologically 'cold' cancer," the researchers reported, "but instead over half of the analyzed [uveal melanoma] metastases harbored tumor-reactive TIL, despite having one of the lowest mutational burdens of any solid cancer and an equally limited responsiveness to approved immunotherapies."
Together, the results pointed to a combination of TIL activation and suppression in the uveal melanoma tumor microenvironment — a notion that was validated in the team's subsequent single-cell transcriptomic and T-cell receptor analyses.
"We found that TILs from metastatic uveal melanoma have the potential to attack the tumor, but something in the tumor microenvironment is shutting them down, so they’re in a dormant, or quiescent, state," Kammula said in a statement. "By liberating these cells from the suppressive environment and growing them in the lab, we can rescue their tumor-fighting capacity when infused back into the patient."
With that in mind, the investigators came up with a so-called "uveal melanoma immunogenomic score" (UMIS) based on the expression of nearly 2,400 immune- and inflammation-related genes. The score identified uveal melanoma samples that contained TILs expected to have activity against the tumor after being isolated, expanded, and used in adoptive cell transfer.
Using single-cell RNA-seq, the team went on to profile the composition of the tumor microenvironment in half a dozen uveal melanoma metastases classified as low or high on the UMIS score. This revealed muted immune cell representation in UMIS-low tumors and enhanced TIL activity in cases classified as UMIS-high.
When the researchers compared UMIS scores with the level of anti-tumor reactivity of TIL cultures expanded from the initial set of metastatic uveal melanoma cases, they saw enhanced tumor-specific activity for TILs from the UMIS-high cases. Those findings were backed up by UMIS profiles for six adoptive TIL therapy responders and 13 non-responders.
"Using a biopsy to calculate a patient's UMIS could help avoid futile therapies and unnecessarily subjecting patients to invasive operations," Kammula said in a statement, adding that the score "offers a window into the tumor that could also help us find the optimal time to treat a patient with adoptive therapy."