1. Preexisting Skin-Resident CD8 and γδ T-cell Circuits Mediate Immune Response in Merkel Cell Carcinoma and Predict Immunotherapy Efficacy.
- Author
-
Reinstein ZZ, Zhang Y, Ospina OE, Nichols MD, Chu VA, Pulido AM, Prieto K, Nguyen JV, Yin R, Moran Segura C, Usman A, Sell B, Ng S, de la Iglesia JV, Chandra S, Sosman JA, Cho RJ, Cheng JB, Ivanova E, Koralov SB, Slebos RJC, Chung CH, Khushalani NI, Messina JL, Sarnaik AA, Zager JS, Sondak VK, Vaske C, Kim S, Brohl AS, Mi X, Pierce BG, Wang X, Fridley BL, Tsai KY, and Choi J more...
- Subjects
- Humans, Immune Checkpoint Inhibitors therapeutic use, Immune Checkpoint Inhibitors pharmacology, Carcinoma, Merkel Cell immunology, Carcinoma, Merkel Cell drug therapy, Carcinoma, Merkel Cell pathology, Carcinoma, Merkel Cell therapy, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Skin Neoplasms immunology, Skin Neoplasms drug therapy, Skin Neoplasms pathology, Skin Neoplasms therapy, Skin Neoplasms genetics, Immunotherapy methods
- 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., (©2024 American Association for Cancer Research.) more...
- Published
- 2024
- Full Text
- View/download PDF