Single-cell transcriptomic profiling for inferring tumor origin and mechanisms of therapeutic resistance

Maoxuan Lin; Moshe Sade-Feldman; Lori Wirth; Michael S Lawrence; Daniel L Faden

doi:10.1038/s41698-022-00314-3

Single-cell transcriptomic profiling for inferring tumor origin and mechanisms of therapeutic resistance

NPJ Precis Oncol. 2022 Oct 10;6(1):71. doi: 10.1038/s41698-022-00314-3.

Authors

Maoxuan Lin^{1

2}, Moshe Sade-Feldman^{2

3

4}, Lori Wirth⁵, Michael S Lawrence^#^{2

3

4}, Daniel L Faden^#^{6

7

8}

Affiliations

¹ Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, 02118, USA.
² Massachusetts General Hospital Cancer Center, Boston, MA, 02118, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁴ Harvard Medical School, Boston, MA, 02115, USA.
⁵ Department of Medicine, Massachusetts General Hospital, Boston, MA, 02118, USA.
⁶ Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, 02118, USA. Daniel_Faden@MEEI.Harvard.edu.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Daniel_Faden@MEEI.Harvard.edu.
⁸ Harvard Medical School, Boston, MA, 02115, USA. Daniel_Faden@MEEI.Harvard.edu.

^# Contributed equally.

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive epithelial cancer with poor overall response rates to checkpoint inhibitor therapy (CPI) despite CPI being the recommended treatment for recurrent or metastatic HNSCC. Mechanisms of resistance to CPI in HNSCC are poorly understood. To identify drivers of response and resistance to CPI in a unique patient who was believed to have developed three separate HNSCCs, we performed single-cell RNA-seq (scRNA-seq) profiling of two responding lesions and one progressive lesion that developed during CPI. Our results not only suggest interferon-induced APOBEC3-mediated acquired resistance as a mechanism of CPI resistance in the progressing lesion but further, that the lesion in question was actually a metastasis as opposed to a new primary tumor, highlighting the immense power of scRNA-seq as a clinical tool for inferring tumor origin and mechanisms of therapeutic resistance.

Abstract

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