Profiling the immune landscape in mucinous ovarian carcinoma

Nicola S Meagher; Phineas Hamilton; Katy Milne; Shelby Thornton; Bronwyn Harris; Ashley Weir; Jennifer Alsop; Christiani Bisinoto; James D Brenton; Angela Brooks-Wilson; Derek S Chiu; Kara L Cushing-Haugen; Sian Fereday; Dale W Garsed; Simon A Gayther; Aleksandra Gentry-Maharaj; Blake Gilks; Mercedes Jimenez-Linan; Catherine J Kennedy; Nhu D Le; Anna M Piskorz; Marjorie J Riggan; Mitul Shah; Naveena Singh; Aline Talhouk; Martin Widschwendter; David D L Bowtell; Francisco J Candido Dos Reis; Linda S Cook; Renée T Fortner; María J García; Holly R Harris; David G Huntsman; Anthony N Karnezis; Martin Köbel; Usha Menon; Paul D P Pharoah; Jennifer A Doherty; Michael S Anglesio; Malcolm C Pike; Celeste Leigh Pearce; Michael L Friedlander; Anna DeFazio; Brad H Nelson; Susan J Ramus

doi:10.1016/j.ygyno.2022.10.022

Profiling the immune landscape in mucinous ovarian carcinoma

Gynecol Oncol. 2023 Jan:168:23-31. doi: 10.1016/j.ygyno.2022.10.022. Epub 2022 Nov 8.

Authors

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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

B7-H1 Antigen* / genetics
CD8-Positive T-Lymphocytes
Carcinoma, Ovarian Epithelial / pathology
Female
Forkhead Transcription Factors / therapeutic use
Humans
Lymphocytes, Tumor-Infiltrating
Ovarian Neoplasms* / drug therapy
Tumor Microenvironment

Substances

B7-H1 Antigen
Forkhead Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding