Treatment of high-grade serous ovarian cancer (HGSOC) remains challenging. Although HGSOC can potentially be responsive to immunotherapy owing to endogenous immunity at the molecular or T cell level, immunotherapy for this disease has fallen short of expectations to date. This Review proposes a working classification for HGSOC based on the presence or absence of intraepithelial T cells, and elaborates the putative mechanisms that give rise to such immunophenotypes. These differences might explain the failures of existing immunotherapies, and suggest that rational therapeutic approaches tailored to each immunophenotype might meet with improved success. In T cell-inflamed tumours, treatment could focus on mobilizing pre-existing immunity and strengthening the activation of T cells embedded in intraepithelial tumour myeloid niches. Conversely, in immune-excluded and immune-desert tumours, treatment could focus on restoring inflammation by reprogramming myeloid cells, stromal cells and vascular epithelial cells. Poly(ADP-ribose) polymerase (PARP) inhibitors, low-dose radiotherapy, epigenetic drugs and anti-angiogenesis therapy are among the tools available to restore T cell infiltration in HGSOC tumours and could be implemented in combination with vaccines and redirected T cells.
This is a preview of subscription content, access via your institution
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Torre, L. A. et al. Ovarian cancer statistics, 2018. CA Cancer J. Clin. 68, 284–296 (2018).
Narod, S. Can advanced-stage ovarian cancer be cured? Nat. Rev. Clin. Oncol. 13, 255–261 (2016).
Vaughan, S. et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat. Rev. Cancer 11, 719–725 (2011).
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Ovarian Tumor Tissue Analysis, C. et al. Dose-response association of CD8+ tumor-infiltrating lymphocytes and survival time in high-grade serous ovarian cancer. JAMA Oncol. 3, e173290 (2017).
Hwang, W. T., Adams, S. F., Tahirovic, E., Hagemann, I. S. & Coukos, G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol. Oncol. 124, 192–198 (2012).
Fridman, W. H., Pages, F., Sautes-Fridman, C. & Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer 12, 298–306 (2012).
Tothill, R. W. et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin. Cancer Res. 14, 5198–5208 (2008).
George, J. et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin. Cancer Res. 19, 3474–3484 (2013).
The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).
Verhaak, R. G. et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J. Clin. Invest. 123, 517–525 (2013).
Chen, G. M. et al. Consensus on molecular subtypes of high-grade serous ovarian carcinoma. Clin. Cancer Res. 24, 5037–5047 (2018).
Hanker, L. C. et al. The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy. Ann. Oncol. 23, 2605–2612 (2012).
Bamias, A. et al. Bevacizumab with or after chemotherapy for platinum-resistant recurrent ovarian cancer: exploratory analyses of the AURELIA trial. Ann. Oncol. 28, 1842–1848 (2017).
Markman, M. The use of bevacizumab in the management of ovarian cancer: an argument for single-agent rather than combination therapy. Ann. Oncol. 22, viii69–viii71 (2011).
Hamanishi, J. et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 33, 4015–4022 (2015).
Matulonis, U. A. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 30, 1080–1087 (2019).
Duraiswamy, J. et al. Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation. Cancer Cell https://doi.org/10.1016/j.ccell.2021.10.008 (2021).
Hornburg, M. et al. Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer. Cancer Cell 39, 928–944 e926 (2021).
Olalekan, S., Xie, B., Back, R., Eckart, H. & Basu, A. Characterizing the tumor microenvironment of metastatic ovarian cancer by single-cell transcriptomics. Cell Rep. 35, 109165 (2021).
Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018).
Ye, Q. et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin. Cancer Res. 20, 44–55 (2014).
Webb, J. R., Milne, K., Watson, P., Deleeuw, R. J. & Nelson, B. H. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin. Cancer Res. 20, 434–444 (2014).
Webb, J. R., Milne, K. & Nelson, B. H. PD-1 and CD103 are widely coexpressed on prognostically favorable intraepithelial CD8 T cells in human ovarian cancer. Cancer Immunol. Res. 3, 926–935 (2015).
Eiva, M. A., Omran., D. K., Chacon, J. & Powell, D. J. Jr Systematic analysis of CD39, CD103, CD137 and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs. Preprint at bioRxiv https://doi.org/10.1101/2021.03.29.437255 (2021).
Desbois, M. et al. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat. Commun. 11, 5583 (2020).
Anadon, C. M. et al. Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells. Cancer Cell https://doi.org/10.1016/j.ccell.2022.03.008 (2022).
Zhang, A. W. et al. Interfaces of malignant and immunologic clonal dynamics in ovarian cancer. Cell 173, 1755–1769 e1722 (2018).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Bobisse, S. et al. Sensitive and frequent identification of high avidity neo-epitope specific CD8+ T cells in immunotherapy-naive ovarian cancer. Nat. Commun. 9, 1092 (2018).
Liu, S. et al. Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer. J. Immunother. Cancer 7, 156 (2019).
D’Angelo, S. P. et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1c259T cells in synovial sarcoma. Cancer Discov. 8, 944–957 (2018).
Siddiqui, I. et al. Intratumoral Tcf1+ PD-1+ CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211 e110 (2019).
Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).
Kroeger, D. R., Milne, K. & Nelson, B. H. Tumor-Infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in ovarian cancer. Clin. Cancer Res. 22, 3005–3015 (2016).
Conejo-Garcia, J. R., Rutkowski, M. R. & Cubillos-Ruiz, J. R. State-of-the-art of regulatory dendritic cells in cancer. Pharmacol. Ther. 164, 97–104 (2016).
Cubillos-Ruiz, J. R. et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell 161, 1527–1538 (2015).
Chopra, S. et al. IRE1alpha-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain. Science https://doi.org/10.1126/science.aau6499 (2019).
Gottlieb, C. E., Mills, A. M., Cross, J. V. & Ring, K. L. Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: a comparison of matched primary and metastatic tumors. Gynecol. Oncol. 144, 607–612 (2017).
Qin, W. et al. The diverse function of PD-1/PD-L pathway beyond cancer. Front. Immunol. 10, 2298 (2019).
Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).
Dangaj, D. et al. Novel recombinant human B7-H4 antibodies overcome tumoral immune escape to potentiate T-cell antitumor responses. Cancer Res. 73, 4820–4829 (2013).
Smith, J. B., Stashwick, C. & Powell, D. J. B7-H4 as a potential target for immunotherapy for gynecologic cancers: a closer look. Gynecol. Oncol. 134, 181–189 (2014).
Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339–1346 (2001).
Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).
Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).
Nielsen, J. S. et al. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 18, 3281–3292 (2012).
Biswas, S. et al. IgA transcytosis and antigen recognition govern ovarian cancer immunity. Nature 591, 464–470 (2021).
Mazor, R. D. et al. Tumor-reactive antibodies evolve from non-binding and autoreactive precursors. Cell 185, 1208–1222 e1221 (2022).
Zhang, Y. et al. Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell 39, 1578–1593 e1578 (2021).
Payne, K. K. et al. BTN3A1 governs antitumor responses by coordinating alphabeta and gammadelta T cells. Science 369, 942–949 (2020).
Crome, S. Q. et al. A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat. Med. 23, 368–375 (2017).
Gonzalez, V. D. et al. High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment. Cell Rep. 36, 109632 (2021).
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
Hong, M. et al. Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control. Cancer Res. 71, 6997–7009 (2011).
Mikucki, M. E. et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat. Commun. 6, 7458 (2015).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Dangaj, D. et al. Cooperation between constitutive and inducible chemokines enables T cell engraftment and immune attack in solid tumors. Cancer Cell 35, 885–900 e810 (2019).
Rodig, S. J. et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aar3342 (2018).
Han, L. Y. et al. HLA class I antigen processing machinery component expression and intratumoral T-Cell infiltrate as independent prognostic markers in ovarian carcinoma. Clin. Cancer Res. 14, 3372–3379 (2008).
Fehlings, M. et al. Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8+ T cells. Nat. Commun. 8, 562 (2017).
Strickland, K. C. et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 7, 13587–13598 (2016).
McAlpine, J. N. et al. BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma. Mod. Pathol. 25, 740–750 (2012).
Bruand, M. et al. Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING. Cell Rep. 36, 109412 (2021).
Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J. Exp. Med. 208, 2005–2016 (2011).
Diamond, M. S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).
Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723 e714 (2017).
Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).
Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).
Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).
Ding, L. et al. PARP inhibition elicits STING-dependent antitumor immunity in Brca1-deficient ovarian cancer. Cell Rep. 25, 2972–2980 e2975 (2018).
Duraiswamy, J., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors — response. Cancer Res. 74, 633–634 (2014).
McGrail, D. J. et al. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann. Oncol. 32, 661–672 (2021).
Moore, K. N. et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J. Clin. Oncol. 39, 1842–1855 (2021).
Farkkila, A. et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat. Commun. 11, 1459 (2020).
Yost, K. E. et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019).
Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).
Zamarin, D. et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG Oncology study. J. Clin. Oncol. 38, 1814–1823 (2020).
Shoushtari, A. N. et al. Measuring toxic effects and time to treatment failure for nivolumab plus ipilimumab in melanoma. JAMA Oncol. 4, 98–101 (2018).
Huang, R. Y. et al. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget 6, 27359–27377 (2015).
Leem, G. et al. 4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-001650 (2020).
Waldhauer, I. et al. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy. MAbs 13, 1913791 (2021).
Scarlett, U. K. et al. In situ stimulation of CD40 and Toll-like receptor 3 transforms ovarian cancer-infiltrating dendritic cells from immunosuppressive to immunostimulatory cells. Cancer Res. 69, 7329–7337 (2009).
Liljenfeldt, L., Dieterich, L. C., Dimberg, A., Mangsbo, S. M. & Loskog, A. S. CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes. Cancer Gene Ther. 21, 95–102 (2014).
Schiza, A. et al. Adenovirus-mediated CD40L gene transfer increases Teffector/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients. J. Transl. Med. 15, 79 (2017).
Morrison, A. H., Diamond, M. S., Hay, C. A., Byrne, K. T. & Vonderheide, R. H. Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity. Proc. Natl Acad. Sci. USA 117, 8022–8031 (2020).
Laman, J. D., Claassen, E. & Noelle, R. J. Functions of CD40 and its ligand, gp39 (CD40L). Crit. Rev. Immunol. 37, 371–420 (2017).
Richman, L. P. & Vonderheide, R. H. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol. Res. 2, 19–26 (2014).
Futagawa, T. et al. Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int. Immunol. 14, 275–286 (2002).
Lin, J. H. et al. Type 1 conventional dendritic cells are systemically dysregulated early in pancreatic carcinogenesis. J. Exp. Med. https://doi.org/10.1084/jem.20190673 (2020).
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
Byrne, K. T. & Vonderheide, R. H. CD40 stimulation obviates innate sensors and drives T cell immunity in cancer. Cell Rep. 15, 2719–2732 (2016).
Lind, N. A., Rael, V. E., Pestal, K., Liu, B. & Barton, G. M. Regulation of the nucleic acid-sensing Toll-like receptors. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00577-0 (2021).
Engel, A. L., Holt, G. E. & Lu, H. The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system. Expert. Rev. Clin. Pharmacol. 4, 275–289 (2011).
Monk, B. J. et al. A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study. Ann. Oncol. 28, 996–1004 (2017).
Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).
Bradley, C. A. CD24 - a novel ‘don’t eat me’ signal. Nat. Rev. Cancer 19, 541 (2019).
Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012).
Tian, L. et al. Targeting Fc receptor-mediated effects and the “don’t eat me” signal with an oncolytic virus expressing an anti-CD47 antibody to treat metastatic ovarian cancer. Clin. Cancer Res. 28, 201–214 (2022).
Shu, R. et al. Engineered CAR-T cells targeting TAG-72 and CD47 in ovarian cancer. Mol. Ther. Oncolytics 20, 325–341 (2021).
Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900 e817 (2020).
Binnewies, M. et al. Targeting TREM2 on tumor-associated macrophages enhances immunotherapy. Cell Rep. 37, 109844 (2021).
Le, D. T. & Jaffee, E. M. Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res. 72, 3439–3444 (2012).
Vlad, A. M. et al. A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer. Cancer Immunol. Immunother. 59, 293–301 (2010).
Edwards, R. P. et al. Comparison of toxicity and survival following intraperitoneal recombinant interleukin-2 for persistent ovarian cancer after platinum: twenty-four-hour versus 7-day infusion. J. Clin. Oncol. 15, 3399–3407 (1997).
Dudley, M. E. et al. CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin. Cancer Res. 16, 6122–6131 (2010).
Rosenberg, S. A. & Dudley, M. E. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr. Opin. Immunol. 21, 233–240 (2009).
Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).
Creelan, B. C. et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat. Med. 27, 1410–1418 (2021).
Stevanovic, S. et al. A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers. Clin. Cancer Res. 25, 1486–1493 (2019).
Kverneland, A. H. et al. Adoptive cell therapy with tumor-infiltrating lymphocytes supported by checkpoint inhibition across multiple solid cancer types. J. Immunother. Cancer https://doi.org/10.1136/jitc-2021-003499 (2021).
Pedersen, M. et al. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study. Oncoimmunology 7, e1502905 (2018).
Kverneland, A. H. et al. Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer. Oncotarget 11, 2092–2105 (2020).
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
Jimenez-Sanchez, A. et al. Unraveling tumor-immune heterogeneity in advanced ovarian cancer uncovers immunogenic effect of chemotherapy. Nat. Genet. 52, 582–593 (2020).
Jimenez-Sanchez, A. et al. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 170, 927–938 e920 (2017).
Joshi, K. et al. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer. Nat. Med. 25, 1549–1559 (2019).
Adams, S. F. et al. Rapid tumor vaccine using Toll-like receptor-activated ovarian cancer ascites monocytes. J. Immunother. Cancer https://doi.org/10.1136/jitc-2020-000875 (2020).
Fujita, K. et al. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin. Cancer Res. 1, 501–507 (1995).
Herrera, F. G. et al. Low dose radiotherapy reverses tumor immune desertification and resistance to immunotherapy. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-21-0003 (2021).
Kunos, C. A. et al. Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group. Gynecol. Oncol. 120, 224–228 (2011).
Fucikova, J. et al. Immunological control of ovarian carcinoma by chemotherapy and targeted anticancer agents. Trends Cancer 8, 426–444 (2022).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Wijayahadi, N., Haron, M. R., Stanslas, J. & Yusuf, Z. Changes in cellular immunity during chemotherapy for primary breast cancer with anthracycline regimens. J. Chemother. 19, 716–723 (2007).
Lo, C. S. et al. Neoadjuvant chemotherapy of ovarian cancer results in three patterns of tumor-infiltrating lymphocyte response with distinct implications for immunotherapy. Clin. Cancer Res. 23, 925–934 (2017).
Bohm, S. et al. Neoadjuvant chemotherapy modulates the immune microenvironment in metastases of tubo-ovarian high-grade serous carcinoma. Clin. Cancer Res. 22, 3025–3036 (2016).
Pujade-Lauraine, E. et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 22, 1034–1046 (2021).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).
Palmer, A. C. & Sorger, P. K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 171, 1678–1691 e1613 (2017).
Shen, J. et al. PARPi triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCAness. Cancer Res. 79, 311–319 (2019).
Monk, B. J. et al. ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer. Int. J. Gynecol. Cancer 31, 1589–1594 (2021).
Ochoa de Olza, M., Navarro Rodrigo, B., Zimmermann, S. & Coukos, G. Turning up the heat on non-immunoreactive tumours: opportunities for clinical development. Lancet Oncol. 21, e419–e430 (2020).
Matei, D. & Nephew, K. P. Epigenetic attire in ovarian cancer: the emperor’s new clothes. Cancer Res. 80, 3775–3785 (2020).
Baretti, M. & Yarchoan, M. Epigenetic modifiers synergize with immune-checkpoint blockade to enhance long-lasting antitumor efficacy. J. Clin. Invest. https://doi.org/10.1172/JCI151002 (2021).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).
Topper, M. J. et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell 171, 1284–1300 e1221 (2017).
Siebenkas, C. et al. Inhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells. PLoS ONE 12, e0179501 (2017).
Odunsi, K. et al. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol. Res. 2, 37–49 (2014).
Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115 e112 (2021).
Sato, E. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538–18543 (2005).
Mariathasan, S. et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).
Tauriello, D. V. F. et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).
Desbois, M. & Wang, Y. Cancer-associated fibroblasts: Key players in shaping the tumor immune microenvironment. Immunol. Rev. 302, 241–258 (2021).
Kochetkova, M. & Samuel, M. S. Differentiation of the tumor microenvironment: are CAFs the organizer? Trends Cell Biol. https://doi.org/10.1016/j.tcb.2021.11.008 (2021).
Eckert, M. A. et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature 569, 723–728 (2019).
Dasari, S., Fang, Y. & Mitra, A. K. Cancer associated fibroblasts: naughty neighbors that drive ovarian cancer progression. Cancers https://doi.org/10.3390/cancers10110406 (2018).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Buckanovich, R. J. et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat. Med. 14, 28–36 (2008).
Bouzin, C., Brouet, A., De Vriese, J., Dewever, J. & Feron, O. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. J. Immunol. 178, 1505–1511 (2007).
Rask, K., Zhu, Y., Wang, W., Hedin, L. & Sundfeldt, K. Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. Mol. Cancer 5, 62 (2006).
Baci, D. et al. The ovarian cancer tumor immune microenvironment (TIME) as target for therapy: a focus on innate immunity cells as therapeutic effectors. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21093125 (2020).
Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).
Rodig, N. et al. Endothelial expression of PD-L1 and PD-L2 down-regulates CD8+ T cell activation and cytolysis. Eur. J. Immunol. 33, 3117–3126 (2003).
Wu, F. H. et al. Endothelial cell-expressed Tim-3 facilitates metastasis of melanoma cells by activating the NF-kappaB pathway. Oncol. Rep. 24, 693–699 (2010).
Huang, X. et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J. Exp. Med. 207, 505–520 (2010).
Zang, X. et al. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod. Pathol. 23, 1104–1112 (2010).
Kraan, J. et al. Endothelial CD276 (B7-H3) expression is increased in human malignancies and distinguishes between normal and tumour-derived circulating endothelial cells. Br. J. Cancer 111, 149–156 (2014).
Qin, X. et al. B7-H3 is a new cancer-specific endothelial marker in clear cell renal cell carcinoma. Onco Targets Ther. 6, 1667–1673 (2013).
Krambeck, A. E. et al. B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc. Natl Acad. Sci. USA 103, 10391–10396 (2006).
Mulligan, J. K. & Young, M. R. Tumors induce the formation of suppressor endothelial cells in vivo. Cancer Immunol. Immunother. 59, 267–277 (2010).
Casos, K. et al. Tumor cells induce COX-2 and mPGES-1 expression in microvascular endothelial cells mainly by means of IL-1 receptor activation. Microvasc. Res. 81, 261–268 (2011).
Taflin, C. et al. Human endothelial cells generate Th17 and regulatory T cells under inflammatory conditions. Proc. Natl Acad. Sci. USA 108, 2891–2896 (2011).
Motz, G. T. & Coukos, G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat. Rev. Immunol. 11, 702–711 (2011).
Motz, G. T. & Coukos, G. Deciphering and reversing tumor immune suppression. Immunity 39, 61–73 (2013).
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
Ohtsu, A. et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J. Clin. Oncol. 29, 3968–3976 (2011).
Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med. 384, 1289–1300 (2021).
Lee, W. S., Yang, H., Chon, H. J. & Kim, C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp. Mol. Med. 52, 1475–1485 (2020).
Burger, R. A., Sill, M. W., Monk, B. J., Greer, B. E. & Sorosky, J. I. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J. Clin. Oncol. 25, 5165–5171 (2007).
Cannistra, S. A. et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J. Clin. Oncol. 25, 5180–5186 (2007).
Rossi, L. et al. Bevacizumab in ovarian cancer: a critical review of phase III studies. Oncotarget 8, 12389–12405 (2017).
Liu, J. F. et al. Assessment of combined nivolumab and bevacizumab in relapsed ovarian cancer: a phase 2 clinical trial. JAMA Oncol. 5, 1731–1738 (2019).
Lee, J. M. et al. Safety and clinical activity of the programmed death-ligand 1 inhibitor durvalumab in combination with poly (ADP-ribose) polymerase inhibitor olaparib or vascular endothelial growth factor receptor 1-3 inhibitor cediranib in women’s cancers: a dose-escalation, phase I study. J. Clin. Oncol. 35, 2193–2202 (2017).
Aghajanian, C. et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J. Clin. Oncol. 30, 2039–2045 (2012).
Coleman, R. L. et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 18, 779–791 (2017).
Ray-Coquard, I. et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N. Engl. J. Med. 381, 2416–2428 (2019).
Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).
Lim, A. R., Rathmell, W. K. & Rathmell, J. C. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife https://doi.org/10.7554/eLife.55185 (2020).
Corbet, C. & Feron, O. Tumour acidosis: from the passenger to the driver’s seat. Nat. Rev. Cancer 17, 577–593 (2017).
Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).
Mendler, A. N. et al. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int. J. Cancer 131, 633–640 (2012).
Pilon-Thomas, S. et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 76, 1381–1390 (2016).
Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).
Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).
Zsiros, E. et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol. 7, 78–85 (2021).
Yakkala, C., Chiang, C. L., Kandalaft, L., Denys, A. & Duran, R. Cryoablation and immunotherapy: an enthralling synergy to confront the tumors. Front. Immunol. 10, 2283 (2019).
Dafni, U. et al. Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: a 20-year systematic review and meta-analysis. Eur. J. Cancer 142, 63–82 (2021).
Harari, A., Graciotti, M., Bassani-Sternberg, M. & Kandalaft, L. E. Antitumour dendritic cell vaccination in a priming and boosting approach. Nat. Rev. Drug Discov. 19, 635–652 (2020).
Chu, C. et al. Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission. Cancer Immunol. Immunother. 61, 629–641 (2012).
Kobayashi, M. et al. The feasibility and clinical effects of dendritic cell-based immunotherapy targeting synthesized peptides for recurrent ovarian cancer. J. Ovarian Res. 7, 48 (2014).
Peethambaram, P. P. et al. A phase 1 trial of immunotherapy with lapuleucel-T (APC8024) in patients with refractory metastatic tumors that express HER-2/neu. Clin. Cancer Res. 15, 5937–5944 (2009).
Romero, P. et al. The human vaccines project: a roadmap for cancer vaccine development. Sci. Transl. Med. 8, 334ps339 (2016).
Kandalaft, L. E. et al. A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer. J. Transl. Med. 11, 149 (2013).
Sarivalasis, A. et al. A Phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma. J. Transl. Med. 17, 391 (2019).
Tanyi, J. L. et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aao5931 (2018).
Tanyi, J. L. et al. Personalized cancer vaccine strategy elicits polyfunctional T cells and demonstrates clinical benefits in ovarian cancer. NPJ Vaccines 6, 36 (2021).
Sarivalasis, A., Morotti, M., Mulvey, A., Imbimbo, M. & Coukos, G. Cell therapies in ovarian cancer. Ther. Adv. Med. Oncol. 13, 17588359211008399 (2021).
Robbins, P. F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).
Kershaw, M. H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).
Haas, A. R. et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol. Ther. 27, 1919–1929 (2019).
Koneru, M., Purdon, T. J., Spriggs, D., Koneru, S. & Brentjens, R. J. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology 4, e994446 (2015).
Luo, H., Xu, X., Ye, M., Sheng, B. & Zhu, X. The prognostic value of HER2 in ovarian cancer: A meta-analysis of observational studies. PLoS ONE 13, e0191972 (2018).
Szender, J. B. et al. NY-ESO-1 expression predicts an aggressive phenotype of ovarian cancer. Gynecol. Oncol. 145, 420–425 (2017).
Dangaj, D. et al. Mannose receptor (MR) engagement by mesothelin GPI anchor polarizes tumor-associated macrophages and is blocked by anti-MR human recombinant antibody. PLoS ONE 6, e28386 (2011).
Lanitis, E., Coukos, G. & Irving, M. All systems go: converging synthetic biology and combinatorial treatment for CAR-T cell therapy. Curr. Opin. Biotechnol. 65, 75–87 (2020).
Macintyre, G. et al. Copy number signatures and mutational processes in ovarian carcinoma. Nat. Genet. 50, 1262–1270 (2018).
Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I. & D’Andrea, A. D. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 5, 1137–1154 (2015).
Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017).
Gulhan, D. C., Lee, J. J., Melloni, G. E. M., Cortes-Ciriano, I. & Park, P. J. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat. Genet. 51, 912–919 (2019).
Polak, P. et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 49, 1476–1486 (2017).
Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 22, 3764–3773 (2016).
Wang, Y. K. et al. Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes. Nat. Genet. 49, 856–865 (2017).
Shah, S. P. Copy number signatures in ovarian cancer. Nat. Genet. 50, 1208–1209 (2018).
Roby, K. F. et al. Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogenesis 21, 585–591 (2000).
Walton, J. et al. CRISPR/Cas9-mediated Trp53 and Brca2 knockout to generate improved murine models of ovarian high-grade serous carcinoma. Cancer Res. 76, 6118–6129 (2016).
Walton, J. B. et al. CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity. Sci. Rep. 7, 16827 (2017).
Iyer, S. et al. Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy. Cancer Discov. 11, 384–407 (2021).
Maniati, E. et al. Mouse ovarian cancer models recapitulate the human tumor microenvironment and patient response to treatment. Cell Rep. 30, 525–540 e527 (2020).
Gitto, S. B. et al. An autologous humanized patient-derived-xenograft platform to evaluate immunotherapy in ovarian cancer. Gynecol. Oncol. 156, 222–232 (2020).
Rongvaux, A. et al. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 32, 364–372 (2014).
Bankert, R. B. et al. Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis. PLoS ONE 6, e24420 (2011).
Sisman, Y., Schnack, T., Hogdall, E. & Hogdall, C. Organoids and epithelial ovarian cancer - a future tool for personalized treatment decisions? (Review). Mol. Clin. Oncol. 16, 29 (2022).
Yang, J. et al. Application of ovarian cancer organoids in precision medicine: key challenges and current opportunities. Front. Cell Dev. Biol. 9, 701429 (2021).
Kim, J. et al. Cell origins of high-grade serous ovarian cancer. Cancers https://doi.org/10.3390/cancers10110433 (2018).
Piek, J. M. et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J. Pathol. 195, 451–456 (2001).
Lee, Y. et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J. Pathol. 211, 26–35 (2007).
Kuhn, E. et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma–evidence supporting the clonal relationship of the two lesions. J. Pathol. 226, 421–426 (2012).
Perets, R. et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in Brca;Tp53;Pten models. Cancer Cell 24, 751–765 (2013).
Cao, Y. et al. ER stress-induced mediator C/EBP homologous protein thwarts effector T cell activity in tumors through T-bet repression. Nat. Commun. 10, 1280 (2019).
Visvanathan, K. et al. Diagnosis of serous tubal intraepithelial carcinoma based on morphologic and immunohistochemical features: a reproducibility study. Am. J. Surg. Pathol. 35, 1766–1775 (2011).
Vang, R. et al. Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma. Int. J. Gynecol. Pathol. 31, 243–253 (2012).
Kuhn, E., Kurman, R. J., Sehdev, A. S. & Shih Ie, M. Ki-67 labeling index as an adjunct in the diagnosis of serous tubal intraepithelial carcinoma. Int. J. Gynecol. Pathol. 31, 416–422 (2012).
Medeiros, F. et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am. J. Surg. Pathol. 30, 230–236 (2006).
Ducie, J. et al. Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma. Nat. Commun. 8, 990 (2017).
Wu, R. C. et al. Genomic landscape and evolutionary trajectories of ovarian cancer precursor lesions. J. Pathol. 248, 41–50 (2019).
Gutkin, D. W. et al. Novel protein and immune response markers of human serous tubal intraepithelial carcinoma of the ovary. Cancer Biomark. 26, 471–479 (2019).
McPherson, A. et al. Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer. Nat. Genet. 48, 758–767 (2016).
Labidi-Galy, S. I. et al. High grade serous ovarian carcinomas originate in the fallopian tube. Nat. Commun. 8, 1093 (2017).
Masoodi, T. et al. Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases. Br. J. Cancer 122, 1219–1230 (2020).
Jamieson, A., Sykes, P., Eva, L., Bergzoll, C. & Simcock, B. Subtypes of stage IV ovarian cancer; response to treatment and patterns of disease recurrence. Gynecol. Oncol. 146, 273–278 (2017).
Bashashati, A. et al. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. J. Pathol. 231, 21–34 (2013).
Hoogstraat, M. et al. Genomic and transcriptomic plasticity in treatment-naive ovarian cancer. Genome Res. 24, 200–211 (2014).
Schwarz, R. F. et al. Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis. PLoS Med. 12, e1001789 (2015).
The authors’ research work is supported by the Ludwig Institute for Cancer Research and NIH grants P50 CA083638 National Cancer Institute Specialized Program of Research Excellence (SPORE) in Ovarian Cancer, R01-CA116779 and R01-CA098951; grants from the Pennsylvania Department of Health (the department specifically disclaims responsibility for any analyses, interpretations or conclusions); and grants from the Ovarian Cancer Immunotherapy Initiative, Ovarian Cancer Research Fund, Sidney Kimmel Foundation, Gynecologic Cancer Foundation, Mary Kay Ash Foundation, Sandy Rollman Ovarian Cancer Foundation, American Cancer Society, Cancer Foundation, Biltema Foundation and Paul Matson Foundation (all to G.C.); partly supported by the Department of Defense (DOD) Early Career Investigator (ECI) W81XWH2210703 Award OC210038 (to D.D.L.) (Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense); and supported by OvaCure and the Rivkin Center for Ovarian Cancer (to L.E.K.).
G.C. declares that he has received grants or research support from or is a co-investigator in clinical trials conducted by Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Iovance, Kite, Roche and Tigen. Lausanne University Hospital has received honoraria for advisory services provided by G.C. to AstraZeneca, Bristol-Myers Squibb, Hoffmann-La Roche, MSD and Geneos Therapeutics. G.C. holds patents related to antibodies and vaccines targeting the tumour vasculature as well as technologies related to T cell expansion and engineering of T cell therapy, for which G.C. receives royalties from the University of Pennsylvania. L.E.K. declares that she has received honoraria for advisory services provided to Geneos Therapeutics and AstraZeneca. D.D.L. declares no competing interests.
Peer review information
Nature Reviews Cancer thanks Rebecca Arend and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Kandalaft, L.E., Dangaj Laniti, D. & Coukos, G. Immunobiology of high-grade serous ovarian cancer: lessons for clinical translation. Nat Rev Cancer (2022). https://doi.org/10.1038/s41568-022-00503-z