Annals of Oncology 28 (Supplement 8): viii1–viii7, 2017

doi:10.1093/annonc/mdx444

SYMPOSIUM ARTICLE

Immunotherapy in ovarian cancer

K. Odunsi
Department of Gynecologic Oncology, Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, USA

Correspondence to: Dr Kunle Odunsi, Department of Gynecologic Oncology, Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA. E-mail:
[email protected]

Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several
critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers
of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor;
(iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and
generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand
whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the
presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients.
Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian
cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid
tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and
adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian
cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore,
a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies,
and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of
immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in
ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune
based strategies for long lasting durable cure.
Key words: immunotherapy, T cells, tumor antigens, NY-ESO-1, cancer vaccines, immunomodulation, adoptive cell therapy

Introduction and background improved understanding of the molecular basis of immune recog-
Ovarian cancer is the most lethal of the gynecologic malignancies. nition and immune regulation of cancer cells. These interventions
Over 22 000 new cases of ovarian cancer are diagnosed each year in include immune checkpoint blockade, cancer vaccines, and adop-
the United States resulting in greater than 14 000 deaths per year tive cell therapy. Indeed, several immune check point inhibitors
[1–3]. Despite aggressive frontline treatments with surgery and ad- were recently approved by the Food and Drug Administration for a
juvant chemotherapy, the 5-year survival rate is <25% for women variety of cancers including melanoma, non-small-cell lung cancer
diagnosed with stages III or IV disease. Although >80% of these (NSCLC), renal cell carcinomas, bladder cancer, and classical
patients will initially have a response to therapy, the majority ultim- Hodgkin lymphoma. Unfortunately, there are currently no
ately recur, and eventually develop chemotherapy-resistant disease. approved immune therapies for ovarian cancer. In this review, the
The results of recent clinical trials, including trials that incorporate current understanding of the host immune response in ovarian
bevacizumab into chemotherapy regimens suggest that a plateau cancer patients will be briefly reviewed. Progress in immune thera-
has been reached for conventional therapies as there is no definitive pies that include cancer vaccines, cell-based therapy, immune
increase in overall survival. Consequently, new treatment strategies checkpoint blockade, and oncolytic virus-based therapy will be dis-
and paradigms are of great need for these patients. Among these, cussed, and we will briefly explore future directions for exploiting
immunotherapy has attracted significant interest with recent immune based strategies for long lasting durable cure.

C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
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Symposium article Annals of Oncology
The host immune response in ovarian human cancers. CTLA-4 regulates T-cell priming and activation,
leading to expansion of auto-reactive T cells, including tumor-
cancer patients
specific T cells. Consequently, anti-CTLA-4 therapies are associ-
Immunologic destruction of tumors is a multistep, coordinated ated with more significant immune-related toxicities compared
process that can be modulated or targeted at several critical with PD-1 blockade. PD-1 is a cell surface receptor that interacts
points to elicit tumor rejection. Although immune rejection of with two known ligands, PD-L1 and PD-L2, resulting in inhib-
ovarian cancer has been demonstrated in several pre-clinical ani- ition of T-cell signaling and cytokine production.
mal models, correlative human studies in patients with ovarian Blockade of these inhibitory receptors with specific antibodies
cancer strongly support a role for immune system involvement in is designed to reinstate an existing antitumor response. This has
patient outcome. been achieved through three general strategies: (i) the inhibition
In an effort to understand whether the immune system plays a of the immunosuppressive receptors expressed by activated T
role in controlling ovarian cancer, our group and others demon- lymphocytes, and (ii) the inhibition of the principal ligands of
strated that the presence of tumor-infiltrating lymphocytes these receptors, such as the PD-1 ligand (PD-L1). Several anti-
(TILs) is associated with improved clinical outcome in ovarian bodies directed against PD-1, PD-L1, and CTLA-4 have been de-
cancer patients [4–6]. Patients with increased frequencies of veloped and are being tested clinically in patients with ovarian
intraepithelial CD8þ TIL (55 versus 26 months, HR ¼ 0.33, 95% cancer. Although these immune checkpoint blocking antibodies
CI 0.18–0.60, P ¼ 0.0003) [4]. A meta-analysis of ten studies with have shown significant promise in mediating tumor regression in
1815 ovarian cancer patients confirmed the observation that a melanoma and other solid tumors, the response rates in ovarian
lack of intraepithelial lymphocytes (TILs) is significantly associ- cancer have been modest. The first published data supporting
ated with a worse survival among ovarian cancer patients [6]. checkpoint inhibitors as a potentially valuable therapeutic ap-
Together, these studies support the notion that tumor infiltration proach in ovarian cancer were observed in trials of the anti-PD-1
by lymphocytes is a reflection of a tumor-related immune re- antibody nivolumab and the anti PD-L1 antibody BMS-93655
sponse. To harness the antitumor immune response, all of the [18]. In the study reported by Hamanishi et al. [19], the best over-
steps in the cancer immunity cycle must be optimal and include all response rate in 20 assessable patients treated with nivolumab
[7–9]: (i) generation of sufficient numbers of effector T cells with was 15% and ae disease control of 45%.
high avidity recognition of tumor antigens in vivo, (ii) trafficking Two additional immune checkpoint trials using the anti-PD-L1
and infiltration into the tumor, (iii) overcoming inhibitory net- antibody avelumab and the anti-PD-1 antibody pembrolizumab
works in the tumor microenvironment, (iv) direct recognition of were presented at the 2015 ASCO annual meeting [20, 21]. Of 75
tumor antigens and generation of an effector antitumor response, heavily pre-treated ovarian cancer patients that received avelumab,
and (v) persistence of the antitumor T cells. 8 patients experienced partial responses, 33 patients had stable dis-
ease, and there were no complete responses, resulting in a disease
control rate of 54.7%. In the KEYNOTE-028 Phase-1b study of
Immune suppressive networks in ovarian pembrolizumab in 26 heavily pre-treated ovarian cancer patients
with a PD-L1 expression level of 1% of tumor cells, the results
cancer showed one complete response, two partial responses, and six pa-
A major barrier to successful deployment of cancer immunother- tients with stable disease, corresponding to a disease control rate of
apy for ovarian cancer patients is the immunosuppressive tumor 34.6%. Ongoing or planned phase 3 trials in ovarian cancer with
microenvironment. Even if large numbers of tumor-specific T immune checkpoint inhibitors include NCT02718417 (Javelin
cells are generated in patients by immunotherapy, these T cells Ovarian 100), ENGOT-ov29-GCIG (ATALANTE), NCT02580058
may not readily destroy tumor targets in vivo. Previous studies by (Javelin Ovarian 200), and NRG-GY009. These trials are testing
our group and others have defined some of the dominant im- combinations with chemotherapy and/or bevacizumab, or the po-
mune resistance mechanisms in ovarian cancer to include extrin- tential efficacy as maintenance therapy.
sic suppression of CD8þ effector cells by regulatory T cells While the initial results of checkpoint inhibitors in ovarian cancer
(Tregs) [4, 10]; metabolic deregulation via tryptophan catabol- are promising, they are modest compared with the spectacular re-
ism by the immunoregulatory enzyme indoleamine-2,3- sults reported for melanoma, renal cell, NSCLC, and bladder cancer.
dioxygenase (IDO) [11, 12]; engagement of the inhibitory recep- Potential mechanisms underpinning the limited antitumor efficacy
tor PD-1 by the ligand PD-L1/B7-H1 [13–15] and development of immune checkpoint inhibitors in ovarian cancer include (i) low
of antigen loss variants [16]; myeloid derived suppressor cells intrinsic tumor immunogenicity and mutational burden in ovarian
[17], and inhibitory cytokines such as TGF-b. Collectively, this compared with other cancers; (ii) expression of multiple co-
redundant immunosuppressive network facilitates tumor pro- inhibitory receptors on T cells infiltrating ovarian cancer; (iii) com-
gression by actively restraining endogenous antitumor immunity pensatory upregulation of multiple immune checkpoints when one
and serves as an important obstacle that must be overcome in of them is blocked; and (iv) redundant immune suppressive mech-
order to implement efficacious immunotherapeutic strategies. anisms (e.g. TGF-b, IDO). All of these factors may counteract the
Evidence in several cancer systems has shown that T-cell ex- beneficial effects of checkpoint blockade. In our studies, we have
pression of inhibitory immune checkpoint receptors is one mech- demonstrated that multiple inhibitory receptors are often co-
anism by which tumors evade or dampen host immunity. These expressed on tumor-antigen specific CD8þ T cells [13]. In human
receptors negatively regulate T-cell function and include CTLA- ovarian cancer, tumor antigen-specific CD8þ TILs co-express PD-1
4, PD-1, LAG-3, TIM-3, TIGIT, and others. Interfering with and LAG-3 and are impaired in IFN-c and TNF-a production com-
CTLA-4 and PD-1 have demonstrated clinical benefit in several pared with PD-1 or LAG-3 single positive cells. Simultaneous

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Annals of Oncology Symposium article
blockade of PD-1 and LAG-3 ex vivo restored effector function to a characterized biologic function, expression of these antigens are
greater extent than single checkpoint blockade, thereby suggesting known to be restricted in immune privileged sites such as the tes-
that monotherapy of checkpoint blockade may not be sufficient for tes, placenta, and fetal ovary, but not in other normal tissues.
eliciting robust antitumor responses. Importantly, we showed that Abnormal expression of these germ-line genes in malignant
blockade of PD-1, LAG-3, or CTLA-4 alone using genetic ablation tumors may reflect the activation of a silenced ‘gametogenic pro-
or blocking antibodies conferred a compensatory upregulation of gram’, which ultimately leads to tumor progression and broad im-
the other checkpoint pathways, potentiating their capacity for local munogenicity [24]. The immunogenicity of CTA has led to
T-cell suppression that, in turn, could be overcome through com- the widespread development of cancer vaccines targeting these
binatorial blockade strategies [15]. Durable antitumor immunity antigens (e.g. NY-ESO-1 and MAGE) in many solid tumors (Table
was most strongly associated with increased numbers of CD8þ 1).
T cells, the frequency of cytokine-producing effector T cells, reduced Among CT antigens, NY-ESO-1 is one of the most spontan-
frequency of Tregs and arginine-expressing monocytic myeloid- eously immunogenic tumor antigens described. The NCI antigen
derived suppressor cells in the peritoneal TME. These data provide a prioritization panel has ranked NY-ESO-1 in the top 10 antigens
basis for combinatorial checkpoint blockade in clinical intervention for further development of immunotherapies. It has two character-
for ovarian cancer. istics that make it a viable candidate: (i) testis-restricted expression
in normal tissues and (ii) its immunogenicity. The initial study of
NY-ESO-1 using a combination of RT-PCR and IHC indicated ab-
Shared tumor antigens, neoantigens, and errant expression of NY-ESO-1 in up to 43% of ovarian cancer pa-
tients [25]. This study was recently extended to more than 1000
cancer vaccines in ovarian cancer ovarian cancer patients and the frequency was confirmed at 40%
In order to generate effector T cells with ability to recognize [26]. The antigen elicits both cellular and humoral immune re-
tumor in vivo, cancer vaccines emerged as an immunotherapeutic sponses in a high proportion of patients with NY-ESO-1-
approach that could harness the immune system in extending re- expressing tumors. Emerging evidence also suggest that NY-ESO-1
mission rates and prevent further malignant growth. The biologic and some additional CT antigens, may be selectively expressed by
principle of cancer vaccines is to stimulate an immune response cancer ‘stem cells’. Therefore, the development of strategies to tar-
specifically directed against malignant cells. In this manner, can- get CT antigens in ovarian cancer could have potential therapeutic
cer vaccines may be used prophylactically and therapeutically. benefit. A number of NY-ESO-1-based clinical trials have been
For prophylactic vaccination, the goal is to mount an immune re- conducted in ovarian cancer patients, and additional trials are on-
sponse that will recognize and eradicate cancer cells early enough going. The vaccines have included long peptides [16, 27], heterol-
to prevent malignant progression. As a complement to the ogous prime boost approach with recombinant vaccinia expressing
prophylactic approach, cancer vaccines may also be used thera- NY-ESO-1 followed by recombinant fowlpox expressing NY-ESO-
peutically to serve as a ‘booster’ for pre-existing antitumor im- 1 [28], and NY-ESO-1 protein in combination with epigenetic
mune responses or activating antitumor immunotherapies that modification [29]. While the individual clinical trials demon-
have been actively administered to the patient. The adaptable na- strated signal of clinical benefit, a recent retrospective combined
ture of cancer vaccines is partially governed by the nature of the analysis of patients on these trials demonstrated a 2-year overall
tumor antigen and has been leveraged to elicit anticancer im- survival advantage for patients with NY-ESO-1 positive tumors
mune responses in a multitude of cancer immunotherapy appli- who receive vaccination, compared with patients with NY-ESO-1
cations. A major question is identifying the most effective and positive tumors who did not receive vaccination [26]. While these
safe vaccine targets in ovarian cancer. results should be interpreted with caution, the conclusion that NY-
Human tumor antigens defined to date can be classified into ESO-1 targeted therapy may be associated with clinical benefit has
one or more of the following categories: (i) differentiation anti- become inescapable, and would need to be tested in randomized
gens that are restricted to very defined tissues, (ii) mutational clinical trials. In the meantime, adoptive transfer of NY-ESO-1
antigens, (iii) amplification antigens, (iv) splice variant antigens, specific T cells is another on-going promising strategy that is dis-
(v) glycolipid antigens, (vi) viral antigens, and (vii) cancer testis cussed in greater detail below.
(CT) antigens. Although there are several options in deciding Advances in next-generation sequencing and epitope prediction
which antigen to target, the fundamental requirements of the now permit the rapid identification of mutant tumor neoantigens.
ideal tumor antigen (TA) include: (i) limited or no expression in This has led to efforts in utilizing these mutant tumor neoantigens
normal tissues, but aberrant expression at high frequencies in for personalizing cancer immunotherapies. Indirect support for this
tumor; (ii) immunogenicity; and (iii) a role in tumor progres- approach comes from studies demonstrating that (i) infusion of au-
sion. While none of the current TAs completely meet all of these tologous ex vivo expanded TILs can induce objective clinical re-
criteria, the family of CT antigens are closest. CT antigens are a sponses in metastatic melanoma [30], and (ii) the relationship
subclass of TAs encoded by 140 genes. The criteria for placing between pre-therapy CD8þ T-cell infiltrates and response to check-
antigens in this category are based on several characteristic fea- point blockade in melanoma [31]. Deep-sequencing technologies
tures [22, 23]: (i) predominant expression in germ cells of the tes- permit easy identification of the mutations present within the
tis and generally not in other normal tissues, (ii) expression in a protein-encoding part of the genome (the exome) of an individual
proportion of malignant tumors of different histological types, tumor allowing for prediction of potential neoantigens. Several pre-
(iii) expression in malignancies in a lineage non-specific fashion, clinical and clinical studies have now confirmed the possibility of
(iv) often mapping of the gene on the X-chromosome, and (v) identifying neoantigens on the basis of cancer exome data [32–36].
often members of multigene families. Despite their poorly Although there are limitations of probing the mutational profile of a

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Symposium article Annals of Oncology
Table 1. Selected ovarian cancer/solid tumor vaccine studies targeting NY-ESO-1

Antigen Phase Disease Technology Co-therapy Sponsor Reference

NY-ESO-1

I Ovarian, fallopian tube DEC-205 Fusion Poly-ICLC, IDO1 Roswell Park Cancer NCT02166905
cancer protein inhibitor Institute
I NY-ESO-1 expressing solid DEC-205 Fusion pro- Rapamycin Roswell Park Cancer NCT01522820
tumors tein/Dendritic cell Institute
I/II NY-ESO-1 expressing DEC-205 Fusion Resiquimod, Celldex Therapeutics NCT00948961
tumors protein Poly-ICLC
I NY-ESO-1 expressing Full length protein Montanide, Mount Sinai School NCT00821652
tumors Resiquimod ofMedicine
I Ovarian, fallopian, primary Peptide Decitabine, Roswell Park Cancer NCT01673217
peritoneal cancer Doxorubicin, Institute
Montanide
I NY-ESO-1/LAGE-1 express- Peptide CpG7909, Ludwig Institute for NCT00199836
ing tumors Montanide Cancer Research
I Ovarian, fallopian, primary Peptide Montanide Memorial Sloan NCT00066729
peritoneal cancer Kettering Cancer
Center
I Ovarian, fallopian, primary Overlapping Long Montanide, Ludwig Institute for NCT00616941
peritoneal cancer peptides (OLP4) Poly-ICLC Cancer Research
I Ovarian, fallopian, primary Vector (ALVAC(2)-NY- GM-CSF, Roswell Park Cancer NCT01536054
peritoneal cancer ESO-1(M) TRICOM) Rapamycin Institute
I Ovarian, fallopian, primary Vector (ALVAC(2)-NY- GM-CSF Ludwig Institute for NCT00803569
peritoneal cancer ESO-1(M) TRICOM) Cancer Research
II Ovarian, fallopian, primary Vector (Fowlpox-NY- Recombinant Ludwig Institute for NCT00112957
peritoneal cancer ESO-1) Vaccinia-NY- Cancer Research
ESO_1

tumor in a single biopsy [37, 38], it is evident that the vast majority for achieving a targeted immune response. In contrast to vaccine
of neoantigens occur within exonic sequence and do not lead to the strategies, ACT is free of the in vivo immune suppressive con-
formation of neoantigens that are recognized by autologous T cells straints that can limit the magnitude, duration, and phenotype of
[38, 39]. Consequently, a robust pipeline for filtering the cancer a desired antitumor immune response achieved by other passive
exome data is essential. Epitope presentation of neoantigens by immunotherapy approaches. T cells used for ACT can be derived
MHC class I molecules may be predicted using previously estab- from peripheral blood lymphocytes (PBL) or TILs. Upon modifi-
lished algorithms that analyze critical features such as the likelihood cation and expansion ex vivo, the activated T cells are re-infused
of proteasomal processing, transport into the endoplasmic reticu- into patients usually after they have received a lymphodepleting
lum, and affinity for the relevant MHC class I alleles. pre-conditioning chemotherapy.
In order to predict epitope abundance, gene and/or protein Initial studies demonstrating the potential of T-cell immuno-
expression levels can also be integrated into the analysis. Based therapy to eradicate solid tumors came from the NCI in studies
on these considerations, it becomes of interest to stimulate of adoptive transfer of in vitro selected TILs. Unfortunately,
neoantigen-specific T-cell responses in cancer patients using two methods of isolating and manufacturing TILs are labor intensive
possible approaches. The first is to synthesize long-peptide vac- and only successful in a subset of patients. In order to improve
cines that encode a set of predicted neoantigens. The second ap- the therapeutic potential of transferred cells, investigators have
proach is to identify and expand pre-existing neoantigen-specific recently focused on genetic modification of PBLs to exhibit
T-cell populations to create either bulk neoantigen-specific T-cell tumor antigen specificity. ACT using genetically engineered PBLs
products or TCR engineered T cells for adoptive therapy. to express antitumor receptors holds promise for extending the
Although the use of neoantigen-based vaccines has not yet been use of ACT to patients with epithelial cancers, such as ovarian
reported in ovarian cancer clinical trials, it is anticipated that cancer.
such clinical trials will be developed in the near future. T cells can be genetically modified to express either (i) a tumor
antigen-specific T-cell receptor (TCR) encoding the a and b
chains with specificity for tumor-restricted peptide expressed on a
given HLA molecule or (ii) a ‘chimeric antigen receptor’ (CAR)
Adoptive T-cell therapy encoding a transmembrane protein comprising the tumor
Adoptive cell therapy (ACT) involves the ex vivo selection of antigen-binding domain of an immunoglobulin linked to one or
antigen-specific T cells and their expansion to desired magnitude more T-cell costimulatory molecules. CAR T cells have also

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Annals of Oncology Symposium article
demonstrated encouraging results of inducing complete response on ovarian cancer patients in first or subsequent remission. The
in 70%–90% of patients with relapsed or refractory B-cell acute success of the trial could lead to the development of a novel strat-
lymphoblastic leukemia. ACT using TCR-engineered T cells have egy to lengthen remission rates in ovarian cancer patients and
resulted in objective responses in the majority of treated patients. minimize the risk of relapse.
In ovarian cancer, there are two on-going trials evaluating the effi- Another promising approach is the development of novel
cacy of TILs (NCT02482090, NCT01883297). Phase I studies of synthetic biology techniques that are leading to a new generation
engineered T cells targeting MUC16 (NCT02498912), mesothelin of TCR or CAR modified T cells. Such strategies include the
(NCT01583686), and NY-ESO-1 (NCT01567891, NCT02457650) incorporation of cytokines such as IL-12 leading to their local
are also on-going. Although spectacular responses have been delivery in the tumor microenvironment [45–48], the inclusion
observed, the majority of clinical responses are short-lived with ul- of decoy receptors for inhibitory molecules such as TGF-b or
timate tumor relapse. A major explanation for this sub-optimal PD-1 [49, 50], and the inclusion of suicide gene to ablate T cells
outcome is the relatively limited long-term survival and effector and abrogate on-going side-effects [51–53]. Hopefully, these
function due to suppression or exhaustion of infused engineered next generation approaches would be tested in ovarian cancer
T cells. in the near future, alone and in combination with other
Recent reports indicate that T cells that are expanded ex vivo to immunotherapies.
maintain more stem-like T-cell populations known as T stem cell Finally, immunotherapy in ovarian cancer will have to consider
memory (Tscm) cells, are capable of a more sustained response the immune suppressive networks within the ovarian tumor
by replenishing effectors. A clear benefit of transferring less ma- microenvironment. Since this is likely to be shaped by the intrin-
ture, more stem-like cells is likely due to increased persistence sic biologic properties of the tumor, a major direction is to
and replenishing capability of these cells in vivo. Conceptually, develop biomarkers that would predict responsiveness to differ-
the regenerative nature of hematopoietic stem cells may provide a ent types of immunotherapies, and allow for treatment selection
long-lasting, potentially life-long supply of effector T cells engin- based on the results. Moreover, such biomarkers would allow
eered against tumor antigens by TCR gene-modification of PBLs. rational combination of immunotherapies, while minimizing
This approach is currently being tested at Roswell Park Cancer toxicities.
Institute in a clinical trial in ovarian cancer patients.

Funding
Conclusions and future directions This work was support by NCI grant P30CA016056, P50CA159981,
R01CA158318, and Roswell Park Alliance Foundation. The publica-
Beyond the PD-1 and CTLA-4 pathways, there are additional tol-
tion of this supplement and the symposium on which it is based
erogenic mechanisms that should be targeted in ovarian cancer as
have been supported through partnership between the Spanish
part of novel combination therapies. For example, one of the
Ovarian Cancer Research Group (GEICO) and the European
most critical tolerogenic mechanisms in ovarian cancer is medi-
Society for Medical Oncology (ESMO).
ated by indole-amine-2,3,-dioxygenase (IDO), an immunoregu-
latory enzyme that catalyzes the rate-limiting step of tryptophan
degradation along the kynurenine pathway. Both the reduction
in local tryptophan levels and the production of tryptophan ca- Disclosure
tabolites that are inhibitory to cells contribute to the immuno- The author has declared no conflicts of interest.
suppressive effects [40], culminating in multipronged negative
effects on T lymphocytes notably on proliferation, function, and
survival. IDO activity also promotes the differentiation of naı̈ve References
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