Profiling the immune landscape in mucinous ovarian carcinoma

Nicola S Meagher¹, Phineas Hamilton², Katy Milne², Shelby Thornton², Bronwyn Harris², Ashley Weir³, Jennifer Alsop⁴, Christiani Bisinoto⁵, James D Brenton⁶, Angela Brooks-Wilson⁷, Derek S Chiu⁸, Kara L Cushing-Haugen⁹, Sian Fereday¹⁰, Dale W Garsed¹⁰, Simon A Gayther¹¹, Aleksandra Gentry-Maharaj¹², Blake Gilks¹³, Mercedes Jimenez-Linan¹⁴, Catherine J Kennedy¹⁵, Nhu D Le¹⁶, Anna M Piskorz⁶, Marjorie J Riggan¹⁷, Mitul Shah⁴, Naveena Singh¹⁸, Aline Talhouk¹⁹, Martin Widschwendter²⁰, David D L Bowtell¹⁰, Francisco J Candido Dos Reis⁵, Linda S Cook²¹, Renée T Fortner²², María J García²³, Holly R Harris²⁴, David G Huntsman²⁵, Anthony N Karnezis²⁶, Martin Köbel²⁷, Usha Menon¹², Paul D P Pharoah⁴, Jennifer A Doherty²⁸, Michael S Anglesio²⁹, Malcolm C Pike³⁰, Celeste Leigh Pearce³¹, Michael L Friedlander³², Anna DeFazio³³, Brad H Nelson², Susan J Ramus³⁴

Affiliations

¹ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia; The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Australia. Electronic address: nicola.meagher@sydney.edu.au.
² Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC, Canada.
³ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁵ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁷ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
⁸ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada.
⁹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁰ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
¹¹ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹² MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹³ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁴ Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
¹⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
¹⁷ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
¹⁸ Department of Pathology, Barts Health National Health Service Trust, London, UK; Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, Canada.
¹⁹ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
²⁰ EUTOPS Institute, University of Innsbruck, Innsbruck, Austria.
²¹ Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA; Community Health Sciences, University of Calgary, Calgary, AB, Canada.
²² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
²⁴ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁵ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
²⁶ Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA, USA.
²⁷ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.
²⁸ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
²⁹ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
³⁰ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Population Health and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
³¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³² School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, New South Wales, Australia; Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, New South Wales, Australia.
³³ The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Australia; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia.
³⁴ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia. Electronic address: s.ramus@unsw.edu.au.

PMID: 36368129
PMCID: PMC10374276
DOI: 10.1016/j.ygyno.2022.10.022

Profiling the immune landscape in mucinous ovarian carcinoma

Nicola S Meagher et al. Gynecol Oncol. 2023 Jan.

. 2023 Jan:168:23-31.

doi: 10.1016/j.ygyno.2022.10.022. Epub 2022 Nov 8.

Authors

Affiliations

¹ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia; The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Australia. Electronic address: nicola.meagher@sydney.edu.au.
² Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, BC, Canada.
³ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
⁴ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁵ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁷ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.
⁸ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada.
⁹ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁰ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
¹¹ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹² MRC Clinical Trials Unit, Institute of Clinical Trials & Methodology, University College London, London, UK.
¹³ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁴ Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
¹⁵ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia.
¹⁶ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
¹⁷ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
¹⁸ Department of Pathology, Barts Health National Health Service Trust, London, UK; Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, Canada.
¹⁹ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
²⁰ EUTOPS Institute, University of Innsbruck, Innsbruck, Austria.
²¹ Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA; Community Health Sciences, University of Calgary, Calgary, AB, Canada.
²² Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
²⁴ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
²⁵ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada.
²⁶ Department of Pathology and Laboratory Medicine, UC Davis Medical Center, Sacramento, CA, USA.
²⁷ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada.
²⁸ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
²⁹ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
³⁰ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Population Health and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
³¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
³² School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, New South Wales, Australia; Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, New South Wales, Australia.
³³ The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Australia; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia.
³⁴ School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia. Electronic address: s.ramus@unsw.edu.au.

PMID: 36368129
PMCID: PMC10374276
DOI: 10.1016/j.ygyno.2022.10.022

Abstract

Objective: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients.

Methods: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration.

Results: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates.

Conclusion: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.

Keywords: Immune infiltrate; Mucinous ovarian carcinoma; Rare histotype.

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Conflict of interest statement

Declaration of Competing Interest NSM has received a travel grant from NanoString technologies, unrelated to this work. DDLB has received research support grants from Roche-Genentech, AstraZeneca, and BeiGene (paid to institution); and personal consulting fees from Exo Therapeutics, that are outside the submitted work. MF has participated in Advisory Boards/Consulting from Astra Zeneca, Novartis, GSK, Takeda, Lilly, MSD Eisei and received honoraria/speakers' fees from AstraZeneca, GSK, ACT-Genomics; Research funding to institution: from AstraZeneca, Novartis, Beigene, all unrelated to this work. ADeF has received funding from AstraZeneca, unrelated this work. NS has received honoraria for invited participation in advisory boards hosted by Astra-Zeneca-MSD and Glaxo SmithKline, unrelated to this work. UM had stock ownership in Abcodia until October 2021, and UCL had a license agreement (2011–2021) with Abcodia not related to this work. BHN is a co-founder of Innovakine Therapeutics Inc., unrelated to this work.

Figures

**Fig. 1.**
Boxplots of statistically significantly different densities in immune phenotypes by tumor epithelium/stromal regions. Difference in mean density calculated using Welch’s t-test.

**Fig. 2.**
Differences in immune cell density by stage (n = 115) and pattern of invasion (n = 90). Panel A: tumor epithelial CD68+/PD-L1+ TAMs (top), tumor epithelial CD68+/PD-L1− TAMs (bottom). Panel B: tumor epithelial PD-L1+ cells (top); stromal PD-L1+ cells (bottom). Panel C: tumor epithelial PD-1+ cells (top); stromal CD8-/FOXP3+ cells (bottom). Differences in mean density calculated using Welch’s t-test.

**Fig. 3.**
A) Unsupervised kmeans clustering of cell densities in tumor epithelium and stroma (n = 76); B) Kaplan-Meier survival curves of overall survival by cluster groups 1‒4 (n = 70). Differences between survival curves calculated using the logrank test.

See this image and copyright information in PMC

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Profiling the immune landscape in mucinous ovarian carcinoma

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Profiling the immune landscape in mucinous ovarian carcinoma

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