Type II refractory coeliac disease (RCD2) is a low-grade intraepithelial lymphoma that may progress to enteropathy-associated T-cell lymphoma (EATL), an aggressive malignancy with poor-prognosis. Progression is not universal and circulating tumor cells are rarely detected in the blood, suggesting that an effective anti-tumor immune response may control the aberrant clones in some patients. This response remains poorly characterized. We performed single-cell transcriptomic and TCR sequencing on 25 duodenal biopsies from RCD2 patients and 24 controls, comprising RCD1, coeliac disease on a gluten-free diet and histologically normal mucosa.
As we previously reported, the aberrant compartment dominated the RCD2 mucosa, with marked inter-patient variation. The remaining immune landscape was itself reshaped: RCD2 biopsies showed increased CD4 and decreased CD8 T cells relative to all three control groups, independent of aberrant cell burden, suggesting a disease-associated shift rather than displacement by the expanding clone. CD8 TCR repertoires were dominated by unique, unexpanded clonotypes and lacked large expansions, while the CD4 repertoires remained indistinguishable from controls, indicating a CD8-restricted phenomenon.
Nonetheless, our preliminary data identified cytotoxic clonal expansions in two RCD2 patients: in one, expansion coincided with a fall in RCD2 tumor burden; in the second, the expanded clone, shared between blood and duodenum, upregulated CD137 and lysed autologous RCD2 tumor cells in co-culture. Interestingly, in a subset of RCD1 patients, T-cell clonotypes shared a transcriptional phenotype with tumoral RCD2 cells, an overlap we aim to exploit to identify biomarkers of pathogenic clones in RCD1.
Together, our analyses reveal an RCD2 mucosa that lacks the cellular and clonal hallmarks of a cytotoxic response to the emerging malignant clone, though isolated cases show that such a response can arise and functionally eliminate tumor cells. The RCD1-RCD2 overlap further supports a biological continuum rather than a categorical distinction, arguing for revisiting how these entities are defined.