Circulating Cancer-Specific CD8 T Cell Frequency Associates with Response to Pd-1 Blockade in Merkel Cell Carcinoma

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 TCR sequencing. In a prospective clinical trial, higher circulating MCPyV-specific CD8 T-cell frequency before anti-PD-1 strongly associated with 2-year recurrence-free survival (75% if detectable, 0% if undetectable, p=0.0018, 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 blood may play a role in anti-PD-1 responses. Thus, strategies that augment their number or mobilize them into tumors could improve outcomes.

Note:
Funding Information: This study was funded by the National Institutes of Health (NIH) National Cancer Institute (NCI) grants P01 CA225517 (PN), F30 CA254168 (THP), T32 CA080416 (SJ), R37 CA251447 (KNS), R01 CA142779 (SLT, DMP), and P30 CA015704 (PN); Odyssey Group Foundation Kelsey Dickson Team Science Courage Research Award: Advancing New Therapies for Merkel Cell Carcinoma (MCC) (A187769) (PN); Bristol Myers Squibb (SLT); National Foundation for Cancer Research (SLT, PN); and the Merkel cell carcinoma (MCC) patient gift fund at the University of Washington (PN).

Declaration of Interests: PN’s institution has received grant support from EMD Serono and Bristol Myers Squibb (BMS), as well as honoraria from Merck and EMD-Serono. DMK, PN, and AC are co-inventors on institutionally-owned patents concerning MCPyV-specific T cell receptors. KNS has received honoraria/consultant fees from Adaptive Biotechnologies; research funding from BMS, AstraZeneca, and Enara Bio; and holds founders’ equity in ManaT Bio, Inc. SLT has received research funding from BMS and consultant fees from PathAI. DMP has received research funding from BMS and Compugen; consultant fees from Amgen, BMS, Compugen, Janssen Pharmaceuticals, Normunity, RAPT Therapeutics, Regeneron, and Tizona LLC; patent royalties through institution from BMS; and owns stocks of Compugen, Mana T Bio, Inc., RAPT Therapeutics, Tizona LCC, and TRex Bio Ltd. No other authors have relevant disclosures.

Ethical Approval Statement: The samples in cohort 1 were collected as part of a neoadjuvant nivolumab trial (NCT02488759). Samples in cohort 2 were collected with informed consent for research use and were approved by the Fred Hutchinson Cancer Center (FHCC) institutional review board, in accordance with the Declaration of Helsinki (2013).

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