Use of CRTAM expression as a predictive biomarker for immune checkpoint blockade in a pan-cancer cohort.
Authors: Miyashita Hirotaka , Nishizaki Daisuke , Lee Suzanna , Nesline Mary K , Conroy Jeffrey M , DePietro Paul , Pabla Sarabjot , Aoshima Ken , Kato Shumei , Kurzrock Razelle 
Published: June 2024

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Background: Immune checkpoint blockade (ICB) has revolutionized the treatment of advanced cancers. Microsatellite instability (MSI) and tumor mutational burden (TMB) are tissue-agnostic predictive biomarkers for ICB. Still, more biomarkers are needed to identify patients who benefit from ICB accurately. Cytotoxic and regulatory T cell molecule (CRTAM) is a transmembrane protein expressed by T cells and NK cells and plays a role in the activation and differentiation of immune cells. The influence of CRTAM expression on the treatment outcome of ICB was analyzed. Methods: A total of 514 patients with various types of cancer included in the Profile-Related Evidence Determining Individualized Cancer Therapy study (NCT02478931) were analyzed. Gene expression levels were normalized to internal housekeeping gene profiles and ranked by percentile. (0 to 100) CRTAM expression was compared with histology, program death ligand 1 (PDL1) immunohistochemistry (IHC), MSI, and TMB. Among them, 217 patients received ICB (ICB cohort), and they were analyzed for overall survival (OS) from diagnosis of advanced/metastatic disease and OS and progression-free survival (PFS) from the first date of ICB. A cohort of patients with advanced melanoma who received nivolumab (N=49) from the GEO database was analyzed for validation (Accession: GSE91061). Results: CRTAM expression was significantly associated with histology, with melanoma and small intestine cancer having the highest expression levels. (p=0.023) CRTAM expression was also associated with PDL1 IHC (≥1%) and MSI-H (p=0.024 and 0.005, respectively), but not with TMB. “High” CRTAM expression was defined by expression levels 75 or greater, and expression levels below 75 were regarded as intermediate/low. 31 patients (15%) showed high CRTAM expression. High CRTAM was significantly associated with longer PFS from ICB initiation in a univariate analysis (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.38-0.92), but not in a multivariate analysis adjusting histology, line of ICB, PDL1 IHC, MSI and TMB. On the other hand, high CRTAM was associated with longer OS from ICB (HR: 0.39, 95% CI: 0.21-0.73), and the significance was preserved in multivariate analysis. OS from advanced/metastatic disease diagnosis was significantly longer in high CRTAM in multivariate analysis in ICB cohort (HR: 0.42, 95% CI: 0.20-0.89), while the association between OS and CRTAM was not observed in patients who did not receive ICB (N=272, HR: 0.76, 95% CI 0.45-1.28). In an external cohort of advanced melanoma, high CRTAM was associated with a higher proportion of objective response in patients treated with nivolumab (42% vs. 14%, p=0.035). Conclusions: CRTAM promotes immune cell activation and differentiation, and high transcriptomic expression correlates with better outcome after ICB, including significantly longer survival in a pan-cancer cohort.