Circulating cancer-specific CD8 T cell frequency is associated with response to PD-1 blockade in Merkel cell carcinoma

Thomas Pulliam; Saumya Jani; Lichen Jing; Heeju Ryu; Ana Jojic; Carolyn Shasha; Jiajia Zhang; Rima Kulikauskas; Candice Church; Charlie Garnett-Benson; Ted Gooley; Aude Chapuis; Kelly Paulson; Kellie N Smith; Drew M Pardoll; Evan W Newell; David M Koelle; Suzanne L Topalian; Paul Nghiem

doi:10.1016/j.xcrm.2024.101412

Circulating cancer-specific CD8 T cell frequency is associated with response to PD-1 blockade in Merkel cell carcinoma

Cell Rep Med. 2024 Feb 20;5(2):101412. doi: 10.1016/j.xcrm.2024.101412. Epub 2024 Feb 10.

Authors

Thomas Pulliam¹, Saumya Jani², Lichen Jing³, Heeju Ryu⁴, Ana Jojic⁴, Carolyn Shasha⁴, Jiajia Zhang⁵, Rima Kulikauskas¹, Candice Church¹, Charlie Garnett-Benson⁶, Ted Gooley⁷, Aude Chapuis⁸, Kelly Paulson⁹, Kellie N Smith⁵, Drew M Pardoll⁵, Evan W Newell¹⁰, David M Koelle¹¹, Suzanne L Topalian¹², Paul Nghiem¹³

Affiliations

¹ Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
² Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98109, USA.
³ Department of Medicine, University of Washington, Seattle, WA 98109, USA.
⁴ Vaccine and Infectious Disease Department, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
⁵ Department of Oncology, Johns Hopkins University, Baltimore, MD 21827, USA; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA.
⁶ Bristol Myers Squibb, Princeton, NJ 08540, USA.
⁷ Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
⁸ Department of Medicine, University of Washington, Seattle, WA 98109, USA; Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
⁹ Paul G. Allen Research Center, Providence-Swedish Cancer Institute, Seattle, WA 98104, USA; Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA.
¹⁰ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98109, USA; Vaccine and Infectious Disease Department, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
¹¹ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA; Vaccine and Infectious Disease Department, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98109, USA; Benaroya Research Institute, Seattle, WA 98101, USA.
¹² The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA.
¹³ Division of Dermatology, Department of Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: pnghiem@uw.edu.

Abstract

Understanding cancer immunobiology has been hampered by difficulty identifying cancer-specific T cells. Merkel cell polyomavirus (MCPyV) causes most Merkel cell carcinomas (MCCs). All patients with virus-driven MCC express MCPyV oncoproteins, facilitating identification of virus (cancer)-specific T cells. We studied MCPyV-specific T cells from 27 patients with MCC using MCPyV peptide-HLA-I multimers, 26-color flow cytometry, single-cell transcriptomics, and T cell receptor (TCR) sequencing. In a prospective clinical trial, higher circulating MCPyV-specific CD8 T cell frequency before anti-PD-1 treatment was strongly associated with 2-year recurrence-free survival (75% if detectable, 0% if undetectable, p = 0.0018; ClinicalTrial.gov: NCT02488759). Intratumorally, such T cells were typically present, but their frequency did not significantly associate with response. Circulating MCPyV-specific CD8 T cells had increased stem/memory and decreased exhaustion signatures relative to their intratumoral counterparts. These results suggest that cancer-specific CD8 T cells in the blood may play a role in anti-PD-1 responses. Thus, strategies that augment their number or mobilize them into tumors could improve outcomes.

Keywords: HLA-I; Merkel cell carcinoma; Merkel cell polyomavirus; acquired resistance; anti-PD-1; cancer-specific T cells; nivolumab; primary resistance; skin cancer.

MeSH terms

CD8-Positive T-Lymphocytes / pathology
Carcinoma, Merkel Cell* / drug therapy
Carcinoma, Merkel Cell* / pathology
Clinical Trials as Topic
Humans
Programmed Cell Death 1 Receptor
Prospective Studies
Skin Neoplasms* / drug therapy
Skin Neoplasms* / pathology

Substances

Programmed Cell Death 1 Receptor