The immune system in the normal endometrium and implications for endometrial cancer development

doi:10.1016/j.jri.2014.12.006

Journal of Reproductive Immunology

Volume 109, June 2015, Pages 7-16

https://doi.org/10.1016/j.jri.2014.12.006 Get rights and content

Highlights

•
The endometrial immune system plays a role in protection against pathogens and feto-maternal tolerance.
•
The endometrial immune system varies according to the stage of the menstrual cycle.
•
Both anti- and pro-tumor immune-related factors are involved in endometrial tumors.
•
Immune system composition may play a role in patient prognosis and may serve as a target for treatment.
•
Immune system plays a dual role in both a healthy situation and a tumor.

Abstract

Although described for the first time some decades ago, the contribution of the immune system to the establishment of tumors has not been extensively pursued for a long time. Over the last decade, however, more and more evidence has been accumulating concerning the role the immune system plays in tumor development and progression and its possible role in patient prognosis. In addition, interest is growing in preclinical and clinical research concerning the use of the immune system in the treatment of cancer. Immunotherapy for gynecological cancers in general, and for endometrial cancer in particular, is still in its infancy. Only a small number of studies, with varying success rates, have been published. Here, we provide a concise overview of the literature available on the role of the immune system in the normal endometrium and in endometrial cancer, in addition to the possible implications for future immunotherapeutic studies.

Introduction

Many risk factors involved in the etiology of endometrial cancer have been described. Obesity and physical inactivity are two significant risk factors for the development of uterine tumors, along with elevated blood pressure, high energy intake, high serum glucose levels and increased exposure to estrogens (Amant et al., 2005). For some of these risk factors, the effects on and interactions with the immune system have been reported. Hormonal fluctuations during the menstrual cycle have been described to modulate immune functions, as reviewed by Wira et al. (2010). Hormonal fluctuations and interactions with immune cells result in a protective environment against invading pathogens, while creating a favorable environment for embryonic implantation and fetal development. Obesity, which is related to an increased risk of developing endometrial cancer, is considered to be a chronic inflammatory state, causing increased release of pro-inflammatory cytokines such as IL-6 and CRP (Visser et al., 1999).

In addition to the effect of the risk factors described on the immune system, the vast majority of endometrial cancer cases are diagnosed in post-menopausal women and often in elderly patients. Age has an important influence on the immune system, the so-called immunosenescence, which parallels hormonal changes that occur with increasing age (Pfister and Savino, 2008). Aging causes an overall decrease in immune-related functions and results in a latent pro-inflammatory state.

Taken together, these data indicate that risk factors associated with the occurrence of endometrial cancer have an important influence on the immune system. In the current review, we provide an overview of the role the immune system plays in the normal non-pregnant uterus and how changes in the immune system may play a role in the development of uterine tumors and the possible clinical outcome. This knowledge is important for successful further development of immunotherapeutic strategies for uterine cancer.

Section snippets

The uterine immune system under physiological conditions and in cancer

The immune system in the normal uterus serves a dual purpose. On the one hand, it plays a role in protection against pathogens, while on the other hand, it has the ability to adapt to an immunosuppressive state in order to create feto-maternal tolerance toward a semi-allogeneic fetus. These separate functions involve the complex interplay of the hormonal fluctuations of the menstrual cycle and the immune system. Normal endometrium is naturally under strict hormonal control. It is under constant

Clinical implications

The currently reviewed data provide an insight into several immune mechanisms in uterine tumors and indicate possible options for therapeutic modalities. The composition of the intratumoral immune infiltrate may have an important influence on treatment outcome. This phenomenon has recently been described in ovarian cancer (Zhang et al., 2003). It was shown that the five-year survival rate of ovarian cancer patients who underwent debulking surgery and received adjuvant chemotherapy was at least

Conclusion

The data outlined here clearly show that the immune system is present and active in both normal endometrium and endometrial tumors. In the normal endometrium, the immune system plays a central role in protection against pathogens and in safeguarding feto-maternal tolerance. Like this dual role in a healthy situation, it also has both a pro- and anti-tumorigenic function. In our opinion, the interplay between positive and negative players and mechanisms in tumor development and progression

Conflict of interest

The authors state to have no financial or commercial conflict of interest.

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MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III–IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m²; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016–004403–31).
From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2–29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7–12·1) in the standard group and 9·6 months (7·2–17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65–0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3–4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]).
Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted.
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None.
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View full text

ReviewThe immune system in the normal endometrium and implications for endometrial cancer development

Highlights

Abstract

Introduction

Section snippets

The uterine immune system under physiological conditions and in cancer

Clinical implications

Conclusion

Conflict of interest

Lancet

Gynecol. Oncol.

Gynecol. Oncol.

Trends Immunol.

Gynecol. Oncol.

Gynecol. Oncol.

Fertil. Steril.

Gynecol. Oncol.

Gynecol. Oncol.

Gynecol. Oncol.

Cell

J. Reprod. Immunol.

Eur. J. Obstet. Gynecol. Reprod. Biol.

Gynecol. Oncol.

Gynecol. Oncol.

J. Steroid Biochem. Mol. Biol.

Hum. Pathol.

Int. Immunopharmacol.

Combined assessment of vascular and myometrial invasion as a model to predict prognosis in stage I endometrioid adenocarcinoma of the uterine corpus

Cancer

Expansion of CD4+ CD25+ and FOXP3+ regulatory T cells during the follicular phase of the menstrual cycle: implications for human reproduction

J. Immunol.

Endometrial cancer, obesity, and body fat distribution

Cancer Res.

The prognostic role of classical and nonclassical MHC class I expression in endometrial cancer

Int. J. Cancer

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

N. Engl. J. Med.

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Cancer

Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin

J. Clin. Endocrinol. Metab.

Morphologic correlates of host response in endometrial carcinoma

Am. J. Reprod. Immunol.

Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms

Nat. Rev. Cancer

Effect of menstrual status on antibacterial activity and secretory leukocyte protease inhibitor production by human uterine epithelial cells in culture

J. Infect. Dis.

Sex hormone modulation of human uterine epithelial cell immune responses

Integr. Comp. Biol.

Antigen presentation by human uterine epithelial cells to autologous T cells

Am. J. Reprod. Immunol.

Expression of MHC products and leucocyte differentiation antigens in gynaecological neoplasms: an immunohistological analysis of the tumour cells and infiltrating leucocytes

Br. J. Cancer

Case-control study of inflammatory markers and the risk of endometrial cancer

Eur. J. Cancer Prev.

Nodal immune reactivity in FIGO (International Federation of Gyn-Ob) Stage I endometrial carcinoma: relationship with myometrial invasion

Acta Obstet. Gynecol. Scand.

Characteristics of tertiary lymphoid structures in primary cancers

Oncoimmunology

Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma

Cancer Res.

Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer

Cancer Immunol. Immunother.

Review
The immune system in the normal endometrium and implications for endometrial cancer development