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Theranostics 2021; 11(11):5092-5106. doi:10.7150/thno.54134 This issue Cite

Research Paper

Single-cell melanoma transcriptomes depicting functional versatility and clinical implications of STIM1 in the tumor microenvironment

Henry Sung-Ching Wong^1,2, Wei-Chiao Chang^1,3,4,5,6✉

1. Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
2. Faculty of Pharmacy, University of Ahmad Dahlan, Yogyakarta, Indonesia.
3. Taipei Medical University Research Center of Cancer Translational Medicine Taipei, Taiwan.
4. Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
5. Division of Nephrology, Department of Internal Medicine; Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.
6. Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

✉ Corresponding author: Wei-Chiao Chang, Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan. Email: wccedu.tw

Abstract

Rationale: Previous studies have implicated the functions of stromal interaction molecule 1 (STIM1) in immunity and malignancy, however, the specificity and effects of STIM1 expression in malignant and non-malignant cells in the tumor microenvironment are unclear.

Methods: In the current study, we posed two central questions: (1) does STIM1 expression elicit different cellular programs in cell types within the melanoma tumor microenvironment (2) whether the expression of STIM1 and STIM1-coexpressed genes (SCGs) serve as prognostic indicators of patient's outcomes? To answer these questions, we dissected cell-specific STIM1-associated cellular programs in diverse cell types within the melanoma tumor microenvironment by measuring cell-type specificity of STIM1 expression and SCGs.

Results: A distinct set of SCGs was highly affected in malignant melanoma cells, but not in the other cell types, suggesting the existence of malignant-cell-specific cellular programs reflected by STIM1 expression. In contrast to malignant cells, STIM1 expression appeared to trigger universal and non-specific biological functions in non-malignant cell types, as exemplified by the transcriptomes of macrophages and CD4⁺ T regulatory cells. Results from bioinformatic analyses indicated that SCGs in malignant cells may alter cell-cell interactions through cytokine/chemokine signaling and/or orchestrate immune infiltration into the tumor. Moreover, a prognostic association between SCGs in CD4⁺ T regulatory cells and patient's outcomes was identified. However, we didn't find any correlation between SCGs and responsiveness of immunotherapy.

Conclusions: Overall, our results provide an integrated biological framework for understanding the functional and clinical consequences of cell-specific STIM1 expression in melanoma.

Keywords: single-cell transcriptomic analysis, stromal interaction molecule 1 (STIM1) melanoma tumor microenvironment, immune landscape.

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