Cancer Testis Antigen Expression Correlates With Immune Activation and Survival in Small Bowel Neuroendocrine Tumors

Abstract

Purpose: Small bowel neuroendocrine tumors (SBNET) frequently present with metastatic disease, and the efficacy of available systemic therapies, especially immune checkpoint blockade, is limited. Toward developing novel immunomodulatory strategies, we interrogated the tumor immune microenvironment of SBNETs using bulk transcriptional and digital spatial profiling (DSP).

Methods: Patients with SBNET who underwent resection from 2003 to 2016 were retrospectively evaluated. Overall survival (OS) was assessed using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariable analysis (MVA). Bulk transcriptional profiling was performed using the NanoString PanCancer-Immune Panel. Whole human transcriptome DSP was performed using PanCK to segment tumor and adjacent stroma.

Results: Unsupervised clustering of gene expression in resected SBNET from 42 patients demonstrated dichotomization by cancer testis antigen (CTA) expression. CTA^high patients (12/42, 29%) demonstrated elevated interleukin expression and had significantly improved OS (hazard ratio, 0.211, 95% CI, 0.059 to 0.751). Increased CTA expression was also associated with objective response to atezolizumab/bevacizumab in patients with neuroendocrine tumors (P = .003). Spatial profiling revealed upregulation of genes involved in immune activation and epigenetic modification in CTA^high tumor regions (all P < .05). Immune deconvolution identified a trend toward increased CD8 T cells, NK cell activation, and dendritic cells in CTA^high tumor regions, whereas T-cell receptor (TCR) profiling revealed marked differences in TCR segment expression between CTA^high and CTA^low regions (P < .001).

Conclusion: High CTA expression in resected SBNET is independently associated with improved survival. Epigenetic dysregulation and immune activation in CTA-enriched tumor regions highlight the potential for combination epigenetic modifiers and immunotherapy in future trials.