Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers

npj Precision Oncology

Article

Emma Titmuss¹  Laura M. Williamson¹  Marco. A. Marra²  Steven J. M. Jones²  Janessa Laskin³  Gun Ho Jang⁴  Julie M. Wilson⁴  Amy Zhang⁴  Grainne M. O’Kane⁵  Steven Gallinger⁵  Barbara Grünwald⁶  Bryn Golesworthy⁷  Tatiana Lenko⁷  Joan Miguel Romero⁷  James Vafiadis⁷  Yifan Wang⁸  George Zogopoulos⁹  Alain Pacis^1,10 

[1] Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada;Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada;Department of Medical Oncology, BC Cancer, Vancouver, BC, Canada;PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada;PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada;Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto, ON, Canada;Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada;Research Institute of the McGill University Health Centre, Montréal, QC, Canada;Rosalind and Morris Goodman Cancer Institute of McGill University, Montréal, QC, Canada;Research Institute of the McGill University Health Centre, Montréal, QC, Canada;Rosalind and Morris Goodman Cancer Institute of McGill University, Montréal, QC, Canada;Department of Surgery, McGill University, Montréal, QC, Canada;Research Institute of the McGill University Health Centre, Montréal, QC, Canada;Rosalind and Morris Goodman Cancer Institute of McGill University, Montréal, QC, Canada;Department of Surgery, McGill University, Montréal, QC, Canada;Department of Oncology, McGill University, Montréal, QC, Canada;Rosalind and Morris Goodman Cancer Institute of McGill University, Montréal, QC, Canada;Canadian Centre for Computational Genomics, McGill University and Genome Québec Innovation Centre, Montréal, QC, Canada;

关键词: ;   

DOI  :  10.1038/s41698-023-00428-2

 received in 2022-12-26, accepted in 2023-07-31,  发布年份 2023

来源: Springer

【 摘 要 】

Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22–0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.

【 授权许可】

CC BY   
© Nature Publishing Group UK 2023

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