IMMUNE MICROENVIRONMENT PROFILING OF PRIMARY ALDOSTERONISM

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Objective: In recent years, remodelling of the immune microenvironment has been documented in aldosterone-producing adenomas (APAs) compared to paired adjacent adrenal cortical tissue. Around 90% of APAs harbour a somatic mutation in known aldosterone-driver genes with the majority harbouring either a KCNJ5 mutation, commonly in solo unilateral APAs, or a CACNA1D mutation, which are also found in aldosterone-producing micronodules, and in bilateral adrenal hyperplasia. Design and method: Herein, we profiled KCNJ5 and CACNA1D mutant APAs for immune cell markers and compared the serum levels of immunoglobulin heavy constant Mu (IGHM) in the AVS samples of unilateral and bilateral primary aldosteronism (PA) patients, and peripheral blood samples of healthy controls (n=20). Results: CD14, a monocyte/macrophage marker, was expressed in APAs and the adrenal medulla at both RNA and protein levels. In APAs, CD14 localized between steroidogenic cells, whereas in the adrenal medulla, it was expressed within chromaffin cells. To note, CD163, a marker for M2 tumour-associated macrophages (TAM), and CD19, a marker for B-cells, were pre-dominant in the CACNA1D mutant APA. Conversely, CD45RA, a marker for naïve T cells, were pre-dominant in KCNJ5 mutant APAs. Co-expression of PD-1 and CD8A, a marker for exhausted cytotoxic T cells, was more in CACNA1D mutant APA compared to KCNJ5 mutant APAs. Lymphatic endothelial cells, a reported inducer of PD-1 expression on CD8 T-cells, were also more present in CACNA1D mutant APA compared to KCNJ5 mutant APAs. In regards to IGHM serum levels, there were significant variability between groups (p=0.007, one-way ANOVA). Post-hoc analysis determined AVS samples from bilateral PA (1.24±2.13 ng/ml) had higher IGHM levels than contralateral AVS samples from unilateral PA (0.12±0.51 ng/ml) and peripheral blood from healthy controls (0.07±0.27 ng/ml; p<0.05). A trend towards higher IGHM levels was observed in bilateral PA compared to AVS samples from affected adrenal glands in unilateral PA (0.29±0.84 ng/ml; p=0.071). Conclusions: In conclusion, the immune system may play a supportive or modulating role in the pathogenesis of PA, especially for CACNA1D mutant APAs. Ongoing research on this role could open potential therapeutic avenues that involve immune-modulating treatments for PA.

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