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

Camelia Quek; Aditya Pratapa; Xinyu Bai; Ghamdan Al-Eryani; Inês Pires da Silva; Aaron Mayer; Nenad Bartonicek; Kate Harvey; Nigel G Maher; Jordan W Conway; Rebecca J Kasalo; Bassem Ben Cheikh; Oliver Braubach; Umaimainthan Palendira; Robyn P M Saw; Jonathan R Stretch; Kerwin F Shannon; Alexander M Menzies; Richard A Scolyer; Georgina V Long; Alexander Swarbrick; James S Wilmott

doi:10.1016/j.celrep.2024.114392

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

Cell Rep. 2024 Jul 23;43(7):114392. doi: 10.1016/j.celrep.2024.114392. Epub 2024 Jun 29.

Authors

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

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.

MeSH terms

Drug Resistance, Neoplasm*
Humans
Immunotherapy* / methods
Melanoma* / immunology
Melanoma* / pathology
Melanoma* / therapy
Multiomics
Single-Cell Analysis*
Tumor Microenvironment* / immunology