Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec 13:11:795547.
doi: 10.3389/fonc.2021.795547. eCollection 2021.

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Laure Chardin  1 , Alexandra Leary  1   2
Affiliations
Review

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

Laure Chardin et al. Front Oncol. .

Abstract

Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.

Keywords: PD-L1; immunosuppression; immunotherapy; ovarian cancer; tumor microenvironment.

PubMed Disclaimer

Conflict of interest statement

AL: fees to institution for ad boards with AZ, Clovis, MSD, GSK, Ability, Merck Serono. AL: support to institution for clinical trials from Roche, GSK, AZ, Agenus, Iovance, Pfizer, MSD, Incyte. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Immunosuppressive tumor microenvironment mediated by Tregs, CAFs and TAMs. OC tumor microenvironment includes antitumor immune cells such as cytotoxic CD8+ T lymphocytes (CD8+ LT), natural killer cells (NK cells) and dendritic cells (DC), and immune tolerant cells such as tumor associated macrophages, cancer associated fibroblasts and regulatory T cells responsible for immune escape. TAMs, CAFs and Tregs express an array of effector molecules that inhibit the antitumor immune responses including cell surface receptors, cytokines, chemokines, and enzymes. Through the expression of immunosuppressive cytokines including TGF-β, IL-6, IL-10 and IL-35, TAMs, CAFs and Tregs inhibit CD8+ LT recruitment, activation and cytotoxicity, promote CD8⁺ LT exhaustion and impede DC maturation. CAFs also reduce antigen presentation function of DC via the secretion of TGF-β, which downregulate the expression of MHC II and co-stimulatory molecules on DC. CAFs can secrete IL-6 and thereby contribute to monocytes recruitment and macrophages differentiation to M2-like phenotype. TGF-β expression by CAFs negatively regulate NK cells activation and cytotoxic activity. FAPhigh CAFs increase differentiation of CD4⁺ cells into CD25+FoxP3+ Tregs and retain them at their surface by expression of OX-40. Tregs constitutively express the co-inhibitory molecule, CTLA-4 which inhibits antigen presentation by binding on CD80 and CD86, co-stimulatory molecules expresses on DC. Tregs also inhibit CD8+ LT activation via IL-2 consumption which is necessary to T-cells activation. The cytokine CCL22 produces by TAMs generate chemokine gradient that induces Treg accumulation in the TME. TAMs also express co-inhibitory molecules such as PD-L1 or B7-1/B7-2 and suppress CD8+ LT cytotoxic activity upon activation with their ligand, PD-1 and CTLA-4. TAMs also impair LT activity though metabolization of L-Arginine which is essential for T-cell function and TCR signaling.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. . Cancer Incidence and Mortality Worldwide: Sources, Methods and Major Patterns in GLOBOCAN 2012. Int J Cancer (2015) 136:E359–386. doi: 10.1002/ijc.29210 - DOI - PubMed
    1. Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al. . Primary Chemotherapy Versus Primary Surgery for Newly Diagnosed Advanced Ovarian Cancer (CHORUS): An Open-Label, Randomised, Controlled, Non-Inferiority Trial. Lancet Lond Engl (2015) 386:249–57. doi: 10.1016/S0140-6736(14)62223-6 - DOI - PubMed
    1. Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. . Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer. N Engl J Med (2010) 363:943–53. doi: 10.1056/NEJMoa0908806 - DOI - PubMed
    1. Bukowski RM, Ozols RF, Markman M. The Management of Recurrent Ovarian Cancer. Semin Oncol (2007) 34:S1–15. doi: 10.1053/j.seminoncol.2007.03.012 - DOI - PubMed
    1. Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. . PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol (2017) 8:561. doi: 10.3389/fphar.2017.00561 - DOI - PMC - PubMed