Abstract
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ∼50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA sequencing (RNA-seq) with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre-and post-ICB. In nonresponders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL1. Responders have increased type I/II interferons and preexisting tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public T-cell receptors. Spatial transcriptomics demonstrated colocalization of T cells with B and dendritic cells, which supply chemokines and costimulation. Lastly, ICB significantly increased clonal expansion or recruitment of Trm and Vδ1 cells in tumors specifically in responders, underscoring their therapeutic importance. These data identify potential clinically actionable biomarkers and therapeutic targets for MCC. Significance: MCC serves as a model of ICB response. We utilized the largest-to-date, multimodal MCC dataset (n = 116 patients) to uncover unique tumor-intrinsic properties and immune circuits that predict response. We identified CD8 Trm and Vδ1 T cells as clinically actionable mediators of ICB response in major histocompatibility complex–high and –low MCCs, respectively.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1631-1652 |
| Number of pages | 22 |
| Journal | Cancer discovery |
| Volume | 14 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2024 |
Funding
This research was made possible through the Division of Research Pathology, Total Cancer Care protocol and supported by the Advanced Analytical Digital Laboratory, Tissue Core, Flow Cytometry Core, and Molecular Genomics Core at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292). Funding support was provided by the Donald A. Adam Melanoma & Skin Cancer Center of Excellence (K.Y. Tsai), the Barry S. Greene Fund (K.Y. Tsai, A.S. Brohl), and the Moffitt Distinguished Scholar Award (N.I. Khushalani). The authors acknowledge the Nanostring Technology Access Program for access to both the GeoMx and CosMx platforms to generate spatial transcriptomic data. We would like to thank the Northwestern Dermatology Clinical Trials Unit for their assistance with tissue acquisition. This work was supported by the Northwestern University Flow Cytometry Core Facility and the Cancer Center Support Grant (NCI CA060553). The research reported in this publication was supported by the Northwestern University Skin Biology & Diseases Resource-Based Center of the National Institutes of Health under the award number P30AR075049. Funding for this study was provided by the National Cancer Institute grant T32 CA009560 and F30CA278298 (Z.Z. Reinstein), National Cancer Institute grant T32 CA233399 (O.E. Ospina, B.L. Fridley), the 2019 AOA Carolyn E. Kuckein Fellowship (Y. Zhang), the V Foundation for Cancer Research grant T2021-019 (J. Choi), the Bakewell Foundation (J. Choi), National Institutes of Health grants DP2 OD024475-01 (J. Choi), the National Comprehensive Cancer Network YIA (J. Choi), R35 GM144083 (B. Pierce), and the Leukemia and Lymphoma Society grant 1377-21 (J. Choi).
ASJC Scopus subject areas
- Oncology
