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Cancer Testis Antigen Expression Correlates With Immune Activation and Survival in Small Bowel Neuroendocrine Tumors
Reed I Ayabe1,2, Y David Seo1,3, Brenda Melendez4
1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
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. CTAhigh 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 CTAhigh tumor regions (all P < .05). Immune deconvolution identified a trend toward increased CD8 T cells, NK cell activation, and dendritic cells in CTAhigh tumor regions, whereas T-cell receptor (TCR) profiling revealed marked differences in TCR segment expression between CTAhigh and CTAlow 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.
Insights
High cancer testis antigen (CTA) expression in small bowel neuroendocrine tumors (SBNET) correlates with better survival and immune activation. This suggests combining epigenetic modifiers with immunotherapy may improve SBNET treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Small bowel neuroendocrine tumors (SBNET) often present with metastatic disease.
- Current systemic therapies, including immune checkpoint blockade, show limited efficacy in SBNET.
- Novel immunomodulatory strategies are needed to improve treatment outcomes.
Purpose of the Study:
- To investigate the tumor immune microenvironment of SBNET.
- To identify potential biomarkers for improved survival and treatment response.
- To explore novel immunomodulatory strategies for SBNET.
Main Methods:
- Retrospective evaluation of 42 SBNET patients who underwent resection.
- Bulk transcriptional profiling using the NanoString PanCancer-Immune Panel.
- Whole human transcriptome digital spatial profiling (DSP) to segment tumor and stroma.
Main Results:
- Unsupervised clustering revealed dichotomization by cancer testis antigen (CTA) expression.
- CTA-high SBNET patients showed elevated interleukin expression and significantly improved overall survival (OS).
- Increased CTA expression was associated with objective response to atezolizumab/bevacizumab and enhanced immune activation in tumor regions.
Conclusions:
- High CTA expression is an independent predictor of improved survival in SBNET.
- CTA-enriched tumor regions exhibit immune activation and epigenetic dysregulation.
- Combination epigenetic modifiers and immunotherapy represent a promising future therapeutic strategy for SBNET.
