Uveal Melanoma Immunogenomic Score Shows Predictive Potential

Udai Kammula, MD, FACS

Investigators have developed a Uveal Melanoma Immunogenomic Score (UMIS) to predict which patients with metastatic uveal melanoma will respond to immunotherapy, according to findings published in Nature Communications.¹

“The dogma was that uveal melanoma is a ‘cold’ cancer, meaning that T cells can’t get into these tumors,” senior author Udai Kammula, MD, FACS, an associate professor of surgery at the University of Pittsburgh and director of the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center, in Pennsylvania, said in a press release.² “We show that T cells are in fact infiltrating metastases and they’re getting activated, but they’re just sitting there in a dormant state because something in the tumor is suppressing them. Adoptive therapy allows us to rescue these cells from the suppressive tumor microenvironment and successfully treat some patients.”

Investigators examined 100 metastases surgically procured from 84 patients with uveal melanoma from tumor infiltrating lymphocyte (TIL) ACT clinical trials at the National Cancer Institute and the University of Pittsburgh Medical Center between 2013 and 2022 (NCT01814046 and NCT03467516). They then developed a UMIS—the median score among the 100 metastases was 0.237 (range, 0.114-0.347)—which was then used as a cutoff to define high and low UMIS groups. Findings demonstrated that the most significantly enriched pathways were in the high UMIS group and involved T cell activation.¹

Patients with metastases scoring above 0.246 had significantly improved progression-free survival and overall survival compared with those with a UMIS below this cutoff.

“If a patient’s UMIS level is below this threshold, we think that adoptive therapy is not appropriate. Using a biopsy to calculate a patient’s UMIS could help avoid futile therapies and unnecessarily subjecting patients to invasive operations,” Kammula said in the press release.² “But the immune system is not static. UMIS offers a window into the tumor that could also help us find the optimal time to treat a patient with adoptive therapy, like picking a fruit when it’s at its ripest.”

Additionally, there were also more lymphoid cells (proportion ratio = 10.50, P = .047) and fewer tumor cells (proportion ratio = 0.88, P = .047) in the metastases with a high UMIS compared with those with a low UMIS. Further, high UMIS metastases were enriched with CD8-positive T cells (proportion ratio = 6.31, P = 6.15e−7) and low UMIS metastases were enriched with CD4-positive T cells (proportion ratio = 0.63, P = 3.32e−4) and T helper/ Th17 T cells (proportion ratio = 0.25, P = .024).¹

Investigators noted that progenitor capability was possible as 9% of the CD8-positive exhausted and 20% of the CD8-positive cytotoxic TIL retained transcriptomic expression of TCF7. Additionally, differential gene expression of the lymphoid cells showed that the high UMIS metastases had upregulation of genes involving T cell activation, T cell exhaustion, lymphocyte activation, interferon response, T cell memory, lymphocyte trafficking, and T cell progenitor capability.

“Taken together, these data demonstrate that the TIL found in high UMIS metastases had undergone activation and effector differentiation consistent with an in vivo adaptive anti-tumor response and indicative of a T cell-inflamed microenvironment,” study authors noted.

The resected metastases evaluated in the study were from 11 anatomic sites with most coming from the liver (56%). Most patients were female (52%) and the median age was 56 years (range, 17-78). Both patients with refractory (76%) and treatment-naive (24%) disease were included in the study. Forty-six patients received prior immune checkpoint therapy; 9 patients received tebentafusp (Kimmtrak) but had no response. Chromosome 3 loss (46%) and 8q gain (85%) were somatic copy number alterations present.

Additional Study Findings

Investigators examined clusters with unique biologic motifs: Cluster A included cellular metabolism pathways, Cluster B immune and inflammatory signaling pathways, Cluster C liver dominant physiologic pathways, and Cluster D cellular signaling and division. Findings revealed that Cluster A was strongly correlated with PC3 (mean rho = +0.76) but was weakly correlated with the negative aspect of PC1 (mean rho = −0.27). Cluster B was exclusively correlated with the negative aspect of PC2 (rho = −0.32) whereas Clusters C and D were not found to independently correlate with PC 1, 2, or 3.

“Given the independent association of PC2 with Cluster B immune pathways, we postulated that PC2 coordinate position was predominantly driven by intrinsic immune and inflammatory gene expression in these metastases,” study authors wrote.

Further findings revealed that the frequency of reactive TIL cultures varied significantly among the total cohort as 55 metastases had measurable anti-tumor reactivity whereas 45 did not. Reactive TIL cultures were also rarely expanded from metastases with a UMIS less than 0.2, which investigators noted suggests “the use of this cutoff as a preoperative threshold to avoid futile surgical resection of noninflamed UM metastases.”

References

1. Leonard-Murali S, Bhaskarla C, Yadav GS, et al. Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility. Nat Commun. 2024;15(1):2863. doi:10.1038/s41467-024-46906-4
2. New insights could unlock immunotherapy for rare, deadly eye cancer. News Release. UPMC Hillman Cancer Center. April 16, 2024. Accessed April 22, 2024. https://www.upmc.com/media/news/041624-deadly-eye-cancer#:~:text=PITTSBURGH%20%E2%80%93%20New%20research%20from%20the,this%20rare%20and%20aggressive%20cancer