Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy

Camelia Quek¹, Aditya Pratapa², Xinyu Bai³, Ghamdan Al-Eryani⁴, Inês Pires da Silva⁵, Aaron Mayer⁶, Nenad Bartonicek⁴, Kate Harvey⁷, Nigel G Maher³, Jordan W Conway³, Rebecca J Kasalo³, Bassem Ben Cheikh², Oliver Braubach², Umaimainthan Palendira⁸, Robyn P M Saw⁹, Jonathan R Stretch⁹, Kerwin F Shannon¹⁰, Alexander M Menzies¹¹, Richard A Scolyer¹², Georgina V Long¹³, Alexander Swarbrick⁴, James S Wilmott¹⁴

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: camelia.quek@melanoma.org.au.
² Akoya Biosciences, Marlborough, MA, USA.
³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁴ Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; School of Clinical Medicine, St Vincent's Clinical Campus, UNSW Medicine & Health, UNSW Sydney, NSW, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, Australia.
⁶ Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA; Enable Medicine, Stanford, CA, USA.
⁷ Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁸ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
⁹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
¹⁰ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Head & Neck Cancer Institute, Chris O'Brien Lifehouse Cancer Centre, Sydney, NSW, Australia.
¹¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
¹² Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital & NSW Health Pathology, Sydney, NSW, Australia.
¹³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
¹⁴ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: james.wilmott@sydney.edu.au.

PMID: 38944836
DOI: 10.1016/j.celrep.2024.114392

Free article

Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy

Camelia Quek et al. Cell Rep. 2024.

Free article

. 2024 Jul 23;43(7):114392.

doi: 10.1016/j.celrep.2024.114392. Epub 2024 Jun 29.

Authors

Affiliations

¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: camelia.quek@melanoma.org.au.
² Akoya Biosciences, Marlborough, MA, USA.
³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁴ Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; School of Clinical Medicine, St Vincent's Clinical Campus, UNSW Medicine & Health, UNSW Sydney, NSW, Australia.
⁵ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, Sydney, Australia.
⁶ Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA; Enable Medicine, Stanford, CA, USA.
⁷ Cancer Ecosystems Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
⁸ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
⁹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
¹⁰ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Head & Neck Cancer Institute, Chris O'Brien Lifehouse Cancer Centre, Sydney, NSW, Australia.
¹¹ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
¹² Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital & NSW Health Pathology, Sydney, NSW, Australia.
¹³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
¹⁴ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: james.wilmott@sydney.edu.au.

PMID: 38944836
DOI: 10.1016/j.celrep.2024.114392

Abstract

Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF⁺SPARCL1⁺ and CENPF⁺ melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.

Keywords: CP: Cancer; CP: Immunology; cancer heterogeneity; checkpoint inhibitor; immune evasion; immunotherapy; lymphoid aggregates; melanoma; single cell sequencing; spatial mapping; therapy resistance; tumor microenvironment.

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Conflict of interest statement

Declaration of interests G.V.L. is a consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd., Pierre Fabre, Provectus, Qbiotics, and Regeneron. R.A.S. has received fees for professional services from SkylineDx BV, IO Biotech ApS, MetaOptima Technology, Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN., Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline. I.P.d.S. is on the advisory board of Merck Sharp & Dohme; has received fees for professional services from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Pierre Fabre; and has had travel support from Bristol Myers Squibb and Merck Sharp & Dohme. R.P.M.S. has received honoraria for advisory board participation from Merck Sharp & Dohme, Novartis, and Qbiotics, and speaking honoraria from Bristol Myers Squibb and Novartis. A.S. has received honoraria for advisory board participation from Nanostring and Phenomic. AI and research support was provided by Nanostring and 10X Genomics.

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Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy

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Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy

Authors

Affiliations

Abstract

Conflict of interest statement

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Medical

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