405MO - Pan-cancer analysis of 4-1BB transcriptome expression and its impact on outcome in patients treated with immune checkpoint inhibitors

Background

Immune checkpoint inhibitors (ICIs) have significantly transformed the landscape of cancer treatment. 4-1BB (CD137; TNFRSF9) is a T cell costimulatory receptor currently being explored as a target for the next generation of immunotherapies. Thus, we conducted a pan-cancer transcriptome analysis of 4-1BB according to various cancer types and immune molecules and evaluated survival outcomes in patients treated with ICIs based on differing 4-1BB expression levels.

Methods

We performed a comprehensive transcriptome analysis of 4-1BB and selected immune molecules in 514 patients with advanced solid tumors at the UCSD Moores Cancer Center. RNA rank expression level for 4-1BB and other immune molecules was classified as “High” (75–100 percentile), “Moderate” (25–74), or “Low” (0–24) for each tumor. Univariate and multivariable logistic analyses for high 4-1BB expression were conducted based on factors such as immune molecules, tumor types, microsatellite instability, and tumor mutational burden. Progression-free survival (PFS) and overall survival (OS) from the start of ICI therapy based on 4-1BB expression level were compared using the Kaplan-Meier method.

Results

Overall, 77 of 514 patients (15%) were classified into “High”, 268 (52%) into “Moderate”, and 169 (33%) into “Low” 4-1BB RNA expression. "High" 4-1BB expression was most often observed in small intestine (25%), ovarian (21%), and lung cancer (20%). In multivariate analysis, "High" PD-L2, ICOS, and CD27 expression were associated with “High” 4-1BB expression. In patients treated with ICIs (n = 217), median PFS was numerically longer among patients with “High” 4-1BB expression (n = 39) versus “Moderate/Low” 4-1BB expression (n = 178) (HR = 0.70, 95% CI: 0.46–1.07); in addition, “High” 4-1BB expression was significantly associated with longer OS (HR = 0.55, 95% CI: 0.33–0.89).

Conclusions

High 4-1BB expression was significantly associated with high RNA expression of other immune markers (PD-L2, ICOS, and CD27) and longer OS from the start of ICI therapy. Ongoing studies combining 4-1BB agonists and other immunotherapy, such as ICIs, may offer increased clinical benefit following comprehensive tumor immune profiling.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Cancer Institute.

Disclosure

All authors have declared no conflicts of interest.