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

• Published in: NPJ precision oncology Vol. 7; no. 1; p. 73
• Main Authors: Romero, Joan Miguel, Titmuss, Emma, Wang, Yifan, Vafiadis, James, Pacis, Alain, Jang, Gun Ho, Zhang, Amy, Golesworthy, Bryn, Lenko, Tatiana, Williamson, Laura M., Grünwald, Barbara, O’Kane, Grainne M., Jones, Steven J. M., Marra, Marco. A., Wilson, Julie M., Gallinger, Steven, Laskin, Janessa, Zogopoulos, George
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/580; 631/67/69; 692/4028/67/327; 692/53/2422; Cancer; Cancer Research; Chemokines; Gene Therapy; Human Genetics; Immunotherapy; Inflammation; Internal Medicine; Lymphocytes; Medicine; Medicine & Public Health; Oncology; Tumors
• ISSN: 2397-768X; 2397-768X
• DOI: 10.1038/s41698-023-00428-2

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-Score hi ) 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-Score hi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Score hi 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.