Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer

Brad H Nelson^{1

2

3}, Phineas Hamilton¹, Minh Tung Phung^{4

5}, Katy Milne¹, Bronwyn Harris¹, Shelby Thornton¹, Donald Stevens¹, Shreena Kalaria^{1

2}, Karanvir Singh¹, Céline M Laumont^{1

3}, Elena Moss¹, Aliya Alimujiang⁴, Nicola S Meagher^{6

7}, Adelyn Bolithon^{6

8}, Sian Fereday^{9

10}, Catherine J Kennedy^{11

12

13}, Joy Hendley⁹, Dinuka Ariyaratne⁹, Kathryn Alsop^{9

10}, Nadia Traficante^{9

11}, Ellen L Goode¹⁴, Anthony Karnezis¹⁵, Hui Shen¹⁶, Jean Richardson^{17

18}, Cindy McKinnonDeurloo¹⁸, Anne Chase¹⁸, Bronwyn Grout¹⁸, Jennifer Anne Doherty¹⁹, Holly R Harris^{20

21}, Kara L Cushing-Haugen²⁰, Michael Anglesio^{22

23}, Karolin Heinze^{22

23}, David Huntsman^{22

24}, Aline Talhouk^{22

23}, Gillian E Hanley^{22

23}, Jennifer Alsop²⁵, Mercedes Jimenez-Linan²⁶, Paul Dp Pharoah²⁷, Jessica Boros^{11

12

13}, Alison H Brand^{12

13}, Paul R Harnett^{13

28}, Raghwa Sharma^{13

29

30}, Jonathan L Hecht³¹, Naoko Sasamoto³², Kathryn L Terry^{32

33}, Beth Karlan³⁴, Jenny Lester³⁴, Michael E Carney³⁵, Marc T Goodman³⁶, Brenda Y Hernandez³⁷, Lynne R Wilkens³⁷, Sabine Behrens³⁸, Renée Turzanski Fortner^{38

39}, Peter A Fasching⁴⁰, Christiani Bisinotto⁴¹, Francisco José Candido Dos Reis⁴¹, Prafull Ghatage⁴², Martin Köbel⁴³, Esther Elishaev⁴⁴, Francesmary Modugno^{45

46

47}, Linda Cook^{48

49}, Nhu Le⁵⁰, Aleksandra Gentry-Maharaj^{51

52}, Usha Menon⁵¹, María J García⁵³, Cristina Rodriguez-Antona^{54

55}, Kyo Farrington⁴³, Linda E Kelemen⁵⁶, Stefan Kommoss⁵⁷, Annette Staebler⁵⁸, Dale W Garsed^{9

10}, James D Brenton⁵⁹, Anna M Piskorz⁵⁹, David Dl Bowtell^{9

10}, Anna DeFazio^{7

11

12

13}, Susan J Ramus^{6

8}, Malcolm C Pike⁶⁰, Celeste Leigh Pearce⁴

Affiliations

¹ Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada.
² Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
³ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁶ School of Clinical Medicine, University of New South Wales (NSW) Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
⁷ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia.
⁸ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁹ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
¹⁰ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
¹¹ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
¹² Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
¹³ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Department of Pathology, University of California Davis School of Medicine, Sacramento, California, USA.
¹⁶ Van Andel Institute, Grand Rapids, Michigan, USA.
¹⁷ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁸ Patient advocate.
¹⁹ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
²⁰ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
²¹ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
²² Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
²³ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, British Columbia, Canada.
²⁴ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
²⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
²⁶ Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom.
²⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, California, USA.
²⁸ Crown Princess Mary Cancer Centre and.
²⁹ Tissue Pathology and Diagnostic Oncology, NSW Health Pathology, Westmead Hospital, Sydney, New South Wales, Australia.
³⁰ Western Sydney University, Sydney, New South Wales, Australia.
³¹ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
³² Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³⁴ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, USA.
³⁵ Department of Obstetrics and Gynecology, John A. Burns School of Medicine University of Hawaii, Honolulu, Hawaii, USA.
³⁶ Cancer Prevention and Control Program, Cedars-Sinai Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
³⁷ University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
³⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁹ Department of Research, Cancer Registry of Norway, Oslo, Norway.
⁴⁰ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁴¹ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁴² Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁴³ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada.
⁴⁴ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴⁵ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.
⁴⁶ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴⁷ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
⁴⁸ Epidemiology, School of Public Health, University of Colorado, Aurora, Colorado, USA.
⁴⁹ Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
⁵⁰ Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
⁵¹ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology and.
⁵² Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
⁵³ Cancer Biology Department, Sols-Morreale Biomedical Research Institute (IIBM), CSIC UAM, Madrid, Spain.
⁵⁴ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
⁵⁵ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
⁵⁶ Division of Acute Disease Epidemiology, South Carolina Department of Health and Environmental Control, Columbia, South Carolina, USA.
⁵⁷ Department of Women's Health and.
⁵⁸ Institute of Pathology and Neuropathology, Tuebingen University Hospital, Tuebingen, Germany.
⁵⁹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
⁶⁰ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

PMID: 39470729
PMCID: PMC11645148
DOI: 10.1172/JCI179501

Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer

Brad H Nelson et al. J Clin Invest. 2024.

. 2024 Oct 29;134(24):e179501.

doi: 10.1172/JCI179501.

Authors

Affiliations

¹ Deeley Research Centre, BC Cancer, Victoria, British Columbia, Canada.
² Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
³ Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁴ School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
⁶ School of Clinical Medicine, University of New South Wales (NSW) Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.
⁷ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia.
⁸ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
⁹ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
¹⁰ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
¹¹ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.
¹² Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
¹³ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
¹⁴ Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
¹⁵ Department of Pathology, University of California Davis School of Medicine, Sacramento, California, USA.
¹⁶ Van Andel Institute, Grand Rapids, Michigan, USA.
¹⁷ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁸ Patient advocate.
¹⁹ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
²⁰ Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
²¹ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
²² Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada.
²³ British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, British Columbia, Canada.
²⁴ Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
²⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
²⁶ Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom.
²⁷ Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, California, USA.
²⁸ Crown Princess Mary Cancer Centre and.
²⁹ Tissue Pathology and Diagnostic Oncology, NSW Health Pathology, Westmead Hospital, Sydney, New South Wales, Australia.
³⁰ Western Sydney University, Sydney, New South Wales, Australia.
³¹ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
³² Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³³ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³⁴ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, California, USA.
³⁵ Department of Obstetrics and Gynecology, John A. Burns School of Medicine University of Hawaii, Honolulu, Hawaii, USA.
³⁶ Cancer Prevention and Control Program, Cedars-Sinai Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
³⁷ University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
³⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁹ Department of Research, Cancer Registry of Norway, Oslo, Norway.
⁴⁰ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany.
⁴¹ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁴² Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁴³ Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, Alberta, Canada.
⁴⁴ Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴⁵ Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA.
⁴⁶ Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁴⁷ Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
⁴⁸ Epidemiology, School of Public Health, University of Colorado, Aurora, Colorado, USA.
⁴⁹ Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
⁵⁰ Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada.
⁵¹ MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology and.
⁵² Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom.
⁵³ Cancer Biology Department, Sols-Morreale Biomedical Research Institute (IIBM), CSIC UAM, Madrid, Spain.
⁵⁴ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
⁵⁵ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
⁵⁶ Division of Acute Disease Epidemiology, South Carolina Department of Health and Environmental Control, Columbia, South Carolina, USA.
⁵⁷ Department of Women's Health and.
⁵⁸ Institute of Pathology and Neuropathology, Tuebingen University Hospital, Tuebingen, Germany.
⁵⁹ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
⁶⁰ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

PMID: 39470729
PMCID: PMC11645148
DOI: 10.1172/JCI179501

Abstract

BACKGROUNDDespite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment.METHODSWe evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.RESULTSPositive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8+ T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.CONCLUSIONThe tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy.FUNDINGOvarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Keywords: Cancer; Cellular immune response; Epidemiology; Immunology; Oncology.

PubMed Disclaimer

Figures

**Figure 1. Heatmap showing pairwise Spearman correlations between immune cell subsets.**
The color scale indicates the strength of the correlation between densities with red indicating high positive correlation. Epi, intraepithelial location; Str, intrastromal location of immune cells.

**Figure 2. Intrastromal versus intraepithelial CD8⁺ TIL densities (cells/mm²) in tumors from all participants and from the STS, MTS, and LTS subgroups.**
The relationship of the intrastromal CD8⁺ density values to the intraepithelial CD8⁺ density values showed no differences between STS and LTS (P = 0.60).

**Figure 3. Violin plots comparing the densities of immune cell subsets in epithelium-high versus –low tumors.**
(A) Density of intraepithelial CD8⁺FoxP3^– T cells in all tumors, epithelium-low tumors, and epithelium-high tumors. (B) Intrastromal CD8⁺FoxP3^– T cells. (C) Intraepithelial PD-1⁺ immune cells. (D) Intrastromal PD-1⁺ immune cells. Embedded box plots indicate median (horizontal line), quartile (box edges), and outliers (points).

**Figure 4. Forest plot of the odds ratios and 95% CIs of LTS compared with STS for intraepithelial immune cell subsets stratified by epithelium-high versus epithelium-low tumors.**

**Figure 5. Multiplex IF images showing CD8⁺ and FoxP3⁺ TILs in epithelium-high versus -low tumors.**
Images further stratified by molecular subtype (C1/MES, C2/IMM and C4/DIF); 2 representative examples of each subgroup are shown. Tumor cells are highlighted by pan-cytokeratin staining (light gray). DAPI staining (blue) detects all cell nuclei. Scale bars: 100 μm. Red, CD8⁺; green, FoxP3⁺.

**Figure 6. Forest plot of the odds ratios and 95% CIs of LTS compared with STS of intraepithelial immune-cell subsets for the C1/MES, C2/IMM, and C4/DIF molecular subtypes in epithelium-high cases.**
Plasma cell results for the C1/MES subtype could not be calculated. The C5/PRO subtype is not presented as several could not be calculated. *P < 0.05 for heterogeneity across subtypes.

See this image and copyright information in PMC

Comment in

Immune-molecular interactions in high-grade serous ovarian cancer distinguish long-term survivors

References

1. Hoppenot C, et al. Who are the long-term survivors of high grade serous ovarian cancer? Gynecol Oncol. 2018;148(1):204–212. doi: 10.1016/j.ygyno.2017.10.032. - DOI - PubMed
1. Saner FAM, et al. Going to extremes: determinants of extraordinary response and survival in patients with cancer. Nat Rev Cancer. 2019;19(6):339–348. doi: 10.1038/s41568-019-0145-5. - DOI - PMC - PubMed
1. Cancer Genome Atlas Research Network Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–615. doi: 10.1038/nature10166. - DOI - PMC - PubMed
1. Ovarian Tumor Tissue Analysis Consortium (OTTA) et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 2017;3(12):e173290. doi: 10.1001/jamaoncol.2017.3290. - DOI - PMC - PubMed
1. Garsed DW, et al. Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian cancer. Clin Cancer Res. 2018;24(3):569–580. doi: 10.1158/1078-0432.CCR-17-1621. - DOI - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer

Affiliations

Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer

Authors

Affiliations

Abstract

Figures

Comment in

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous