Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

Darci Phillips, Magdalena Matusiak, Belén Rivero Gutierrez, Salil S. Bhate, Graham L. Barlow, Sizun Jiang, Janos Demeter, Kimberly S. Smythe, Robert H. Pierce, Steven P. Fling, Nirasha Ramchurren, Martin A. Cheever, Yury Goltsev, Robert B. West, Michael S. Khodadoust, Youn H. Kim, Christian M. Schürch () and Garry P. Nolan ()
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Darci Phillips: Stanford University School of Medicine
Magdalena Matusiak: Stanford University School of Medicine
Belén Rivero Gutierrez: Stanford University School of Medicine
Salil S. Bhate: Stanford University School of Medicine
Graham L. Barlow: Stanford University School of Medicine
Sizun Jiang: Stanford University School of Medicine
Janos Demeter: Stanford University School of Medicine
Kimberly S. Smythe: Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center
Robert H. Pierce: Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center
Steven P. Fling: Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center
Nirasha Ramchurren: Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center
Martin A. Cheever: Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center
Yury Goltsev: Stanford University School of Medicine
Robert B. West: Stanford University School of Medicine
Michael S. Khodadoust: Stanford University School of Medicine
Youn H. Kim: Stanford University School of Medicine
Christian M. Schürch: Stanford University School of Medicine
Garry P. Nolan: Stanford University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1+ CD4+ T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.

Date: 2021
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DOI: 10.1038/s41467-021-26974-6

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