Abstract
While immune checkpoint-based immunotherapy (ICI) shows promising clinical results in patients with cancer, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and nonmalignant cells. Although insights into the mechanisms that modulate the pivotal antitumoral activity of cytotoxic T cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types. Here, we used multiplexed IHC to spatially characterize the immune landscape of metastatic melanoma from responders and nonresponders to ICI. Such high-dimensional pathology maps showed that Tcy gradually evolve toward an exhausted phenotype as they approach and infiltrate the tumor. Moreover, a key cellular interaction network functionally linked Tcy and PD-L1+ macrophages. Mapping the respective spatial distributions of these two cell populations predicted response to anti-PD-1 immunotherapy with high confidence. These results suggest that baseline measurements of the spatial context should be integrated in the design of predictive biomarkers to identify patients likely to benefit from ICI. SIGNIFICANCE: This study shows that spatial characterization can address the challenge of finding efficient biomarkers, revealing that localization of macrophages and T cells in melanoma predicts patient response to ICI. See related commentary by Smalley and Smalley, p. 3198.
Original language | English |
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Pages (from-to) | 3275-3290 |
Number of pages | 16 |
Journal | Cancer Research |
Volume | 82 |
Issue number | 18 |
Early online date | 14 Jul 2022 |
DOIs | |
Publication status | Published (in print/issue) - 15 Sept 2022 |
Bibliographical note
A. Antoranz was partially funded by the KU Leuven funding (C3/19/053), Opening the Future Campaign of the KU Leuven University Fund, and by Kom op tegen Kanker (Stand Up To Cancer), the Flemish cancer society. F.M. Bosisio was funded by KUL INTERNE FONDSEN MIDDEL-Zware infrastructuren EMHD8191-AKUL/19/30 I005920N, FWO Fundamenteel Klinisch Mandaat EMHD8972-FKM/20, Impulsbudget UZ Leuven 2018. W.M. Gallagher, S.M. Lynch, and A. Rahman were funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement #642295 (MEL-PLEX), by the European Union’s FP7 Marie Skłodowska-Curie Industry-Academia Partnership and Pathways research programme under the grant agreement #611107 (SYS-MEL), and by the Science Foundation Ireland Investigator Programme (OPTi-PREDICT; 15/IA/3104) and the Science Foundation Ireland Strategic Partnership Programme (Precision Oncology Ireland; 18/SPP/ 3522). M.M. Bolognesi and G. Cattoretti were funded by the Regione Lombardia POR FESR 2014–2020, Call HUB Ricerca ed Innovazione: ImmunHUB.Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research.
Funding Information:
A. Antoranz reports grants from Kom op teger kanker during the conduct of the study; in addition, A. Antoranz has a patent for European patent application EP22182632.4 filed on July 1, 2022 pending. W.M. Gallagher reports grants from European Union, European Union, Science Foundation Ireland, and Science Foundation Ireland during the conduct of the study and other support from OncoMark and OncoAssure outside the submitted work. F. De Smet reports grants from Kom op tegen kanker, Flanders Research Foundation (FWO), KU Leuven, and Leuven Cancer Institute during the conduct of the study. F.M. Bosisio reports grants from Kom op tegen kanger, FWO, and UZ Leuven during the conduct of the study; in addition, F.M. Bosisio has a patent for European patent application EP22182632.4 filed on July 1, 2022 pending. No disclosures were reported by the other authors.
Funding Information:
A. Antoranz was partially funded by the KU Leuven funding (C3/19/053), Opening the Future Campaign of the KU Leuven University Fund, and by Kom op tegen Kanker (Stand Up To Cancer), the Flemish cancer society. F.M. Bosisio was funded by KUL INTERNE FONDSEN MIDDEL-Zware infrastructuren EMH-D8191-AKUL/19/30 I005920N, FWO Fundamenteel Klinisch Mandaat EMH-D8972-FKM/20, Impulsbudget UZ Leuven 2018. W.M. Gallagher, S.M. Lynch, and A. Rahman were funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement #642295 (MEL-PLEX), by the European Union’s FP7 Marie Skłodowska-Curie Industry-Academia Partnership and Pathways research programme under the grant agreement #611107 (SYS-MEL), and by the Science Foundation Ireland Investigator Programme (OPTi-PREDICT; 15/IA/3104) and the Science Foundation Ireland Strategic Partnership Programme (Precision Oncology Ireland; 18/SPP/ 3522). M.M. Bolognesi and G. Cattoretti were funded by the Regione Lombardia POR FESR 2014–2020, Call HUB Ricerca ed Innovazione: ImmunHUB.
Funding Information:
A. Antoranz was partially funded by the KU Leuven funding (C3/19/053), Opening the Future Campaign of the KU Leuven University Fund, and by Kom op tegen Kanker (Stand Up To Cancer), the Flemish cancer society. F.M. Bosisio was funded by KUL INTERNE FONDSEN MIDDEL-Zware infrastructuren EMHD8191-AKUL/19/30 I005920N, FWO Fundamenteel Klinisch Mandaat EMHD8972-FKM/20, Impulsbudget UZ Leuven 2018. W.M. Gallagher, S.M. Lynch, and A. Rahman were funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement #642295 (MEL-PLEX), by the European Union’s FP7 Marie Skłodowska-Curie Industry-Academia Partnership and Pathways research programme under the grant agreement #611107 (SYS-MEL), and by the Science Foundation Ireland Investigator Programme (OPTi-PREDICT; 15/IA/3104) and the Science Foundation Ireland Strategic Partnership Programme (Precision Oncology Ireland; 18/SPP/ 3522). M.M. Bolognesi and G. Cattoretti were funded by the Regione Lombardia POR FESR 2014–2020, Call HUB Ricerca ed Innovazione: ImmunHUB. The authors would like to acknowledge the technical support of Dr. John A. Browne, UCD School of Agriculture and Food Science.
Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research.
Keywords
- B7-H1 Antigen/genetics
- Biomarkers
- Cell Communication
- Humans
- Immunologic Factors/therapeutic use
- Immunotherapy/methods
- Melanoma/drug therapy
- Neoplasms, Second Primary