Bridging the divide: unveiling mutual immunological pathways of cancer and pregnancy.

The juxtaposition of two seemingly disparate physiological phenomena within the human body-namely, cancer and pregnancy-may offer profound insights into the intricate interplay between malignancies and the immune system. Recent investigations have unveiled striking similarities between the pivotal processes underpinning fetal implantation and successful gestation and those governing tumor initiation and progression. Notably, a confluence of features has emerged, underscoring parallels between the microenvironment of tumors and the maternal-fetal interface. These shared attributes encompass establishing vascular networks, cellular mobilization, recruitment of auxiliary tissue components to facilitate continued growth, and, most significantly, the orchestration of immune-suppressive mechanisms.Our particular focus herein centers on the phenomenon of immune suppression and its protective utility in both of these contexts. In the context of pregnancy, immune suppression assumes a paramount role in shielding the semi-allogeneic fetus from the potentially hostile immune responses of the maternal host. In stark contrast, in the milieu of cancer, this very same immunological suppression fosters the transformation of the tumor microenvironment into a sanctuary personalized for the neoplastic cells.Thus, the striking parallels between the immunosuppressive strategies deployed during pregnancy and those co-opted by malignancies offer a tantalizing reservoir of insights. These insights promise to inform novel avenues in the realm of cancer immunotherapy. By harnessing our understanding of the immunological events that detrimentally impact fetal development, a knowledge grounded in the context of conditions such as preeclampsia or miscarriage, we may uncover innovative immunotherapeutic strategies to combat cancer.

Heregulin (HRG) assessment for clinical trial eligibility testing in a molecular registry (PRAEGNANT) in Germany.

BACKGROUND: Eligibility criteria are a critical part of clinical trials, as they define the patient population under investigation. Besides certain patient characteristics, clinical trials often include biomarker testing for eligibility. However, patient-identification mostly relies on the trial site itself and is often a time-consuming procedure, which could result in missing out on potentially eligible patients. Pre-selection of those patients using a registry could facilitate the process of eligibility testing and increase the number of identified patients. One aim with the PRAEGNANT registry (NCT02338167) is to identify patients for therapies based on clinical and molecular data. Here, we report eligibility testing for the SHERBOC trial using the German PRAEGNANT registry. METHODS: Heregulin (HRG) has been reported to identify patients with better responses to therapy with the anti-HER3 monoclonal antibody seribantumab (MM-121). The SHERBOC trial investigated adding seribantumab (MM-121) to standard therapy in patients with advanced HER2-negative, hormone receptor-positive (HR-positive) breast cancer and HRG overexpression. The PRAEGNANT registry was used for identification and tumor testing, helping to link potential HRG positive patients to the trial. Patients enrolled in PRAEGNANT have invasive and metastatic or locally advanced, inoperable breast cancer. Patients eligible for SHERBOC were identified by using the registry. Study aims were to describe the HRG positivity rate, screening procedures, and patient characteristics associated with inclusion and exclusion criteria. RESULTS: Among 2769 unselected advanced breast cancer patients, 650 were HER2-negative, HR-positive and currently receiving first- or second-line treatment, thus potentially eligible for SHERBOC at the end of current treatment; 125 patients also met further clinical eligibility criteria (e.g. menopausal status, ECOG). In the first/second treatment lines, patients selected for SHERBOC based on further eligibility criteria had a more favorable prognosis than those not selected. HRG status was tested in 38 patients, 14 of whom (36.8%) proved to be HRG-positive. CONCLUSION: Using a real-world breast cancer registry allowed identification of potentially eligible patients for SHERBOC focusing on patients with HER3 overexpressing, HR-positive, HER2-negative metastatic breast cancer. This approach may provide insights into differences between patients eligible or non-eligible for clinical trials. TRIAL REGISTRATION: Clinicaltrials, NCT02338167 , Registered 14 January 2015 - retrospectively registered.

Multiple eruptive dermatofibromas associated with pregnancy- a case and literature review.

Dermatofibromas are common and asymptomatic benign histiocytic tumors. The occurrence in a small number (up to 5 lesions) is frequent. However, the expression "multiple eruptive dermatofibromas" is reserved for the appearance of more than 5 lesions in less than four months. Multiple eruptive dermatofibromas are rare and usually associated with an underlying systemic condition, the most common being autoimmune diseases or HIV infection. Herein we report multiple eruptive dermatofibromas developing in an otherwise healthy pregnant woman. Although the pathogenesis of this condition remains unknown, it is believed to be related to immunological alterations, given the strong association with states of immunosuppression or, in the case of pregnancy, with a state of immunotolerance.

The immune response in pregnancy and in cancer is active and supportive of placental and tumor cell growth not their destruction.

While many investigators have described the biochemical and physiological similarities between tumor cells and trophoblast cells, in this discourse we will compare primarily their leucocytes, which constitute a large portion of the tumor and its microenvironment as well as the placenta and its microenvironment. There is a remarkable similarity between the cells that support placental growth and development and tumor growth and development. In many cases over half of the cells present in the tumor and the placenta are non-tumor or nontrophoblast cells, immune cells. Most of these immune cells are prevented from attacking the fetal derived placental cells and the self-derived tumor cells. Nevertheless, these leucocytes, in our opinion, are very active and support tumor and placental cell growth through the production of growth factors and angiogenic factors. These cells do this by activating the portion of the immune response which initiates and helps control tissue repair.

Immunologically silent cancer clone transmission from mother to offspring.

Rare cases of possible materno-fetal transmission of cancer have been recorded over the past 100 years but evidence for a shared cancer clone has been very limited. We provide genetic evidence for mother to offspring transmission, in utero, of a leukemic cell clone. Maternal and infant cancer clones shared the same unique BCR-ABL1 genomic fusion sequence, indicating a shared, single-cell origin. Microsatellite markers in the infant cancer were all of maternal origin. Additionally, the infant, maternally-derived cancer cells had a major deletion on one copy of chromosome 6p that included deletion of HLA alleles that were not inherited by the infant (i.e., foreign to the infant), suggesting a possible mechanism for immune evasion.

Breast Cancer during Pregnancy as a Special Type of Early-Onset Breast Cancer: Analysis of the Tumor Immune Microenvironment and Risk Profiles.

Breast cancer during pregnancy (PrBC) is a rare tumor with only a little information on its immune landscape. Here, we sought to characterize the cellular composition of the tumor microenvironment (TME) of PrBC and identify its differences from early-onset breast cancer (EOBC) in non-pregnant women. A total of 83 PrBC and 89 EOBC were selected from our Institutional registry and subjected to tumor-infiltrating lymphocytes (TILs) profiling and immunohistochemistry for CD4, CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) (clone 22C3). A significantly lower frequency of hormone receptor (HR)-positive tumors was observed in PrBC. The prevalence of low/null PD-L1 and CD8+TILs was higher in PrBC than in the controls, specifically in HR+/HER2- breast cancers. PrBC had a significantly higher risk of relapse and disease-related death, compared to EOBC. The presence of TILs and each TIL subpopulation were significantly associated with disease relapse. Moreover, the death rate was higher in PrBC with CD8+ TILs. The TME of PrBC is characterized by specific patterns of TIL subpopulations with significant biological and prognostic roles. Routine assessment of TILs and TILs subtyping in these patients would be a valid addition to the pathology report that might help identify clinically relevant subsets of women with PrBC.

Low concordance between positive antibodies to thyroperoxidase and thyroid ultrasound autoimmune pattern in pregnant women.

The diagnostic and prognostic role of thyroid ultrasound (TUS) in pregnant women positive for antibodies to thyroperoxidase (TPOAb) is unclear. The aim of our study was to compare the relation of ultrasound thyroid texture to the thyroid laboratory tests in pregnant women and controls. Using a semi-quantitative assessment we compared TUS in two groups of women with positive TPOAb and/or with thyroid dysfunction (TSH out of 0.06-3.67 mIU/L): 186 women in 1(st) trimester of pregnancy recruited from universal screening and 67 asymptomatic age-comparable non-pregnant non-postpartum women recruited from screening of general population (controls). Women with previous history of thyroid diseases were excluded. Only 64/131 (48.9 %) of TPOAb-positive pregnant women were TUS-positive (TUS with autoimmune pattern) in comparison with 35/49 (71.4 %) TPOAb-positive controls (p <0.011). Pregnant women had more often TSH >10.0 mIU/L if they were TPOAb-positive/TUS-positive as compared to those TPOAb-positive/TUS-negative (8/64 (12.5 %) vs. 0/67 (0 %), p = 0.009). The prevalence of preterm deliveries among TPOAb-positive women was significantly lower if TPOAb-positivity was not accompanied by TUS-positivity (2/67 (3.0 %) vs. 10/64 (15.6 %) in TPOAb-positive/TUS-positive women, p = 0.028). In conclusion, nearly half of the TPOAb-positive pregnant women did not have an autoimmune pattern in TUS. Normal TUS image in TPOAb-positive pregnant women might be a protective factor for preterm delivery.

Pregnancy-Induced Alterations in NK Cell Phenotype and Function.

Pregnant women are particularly susceptible to complications of influenza A virus infection, which may result from pregnancy-induced changes in the function of immune cells, including natural killer (NK) cells. To better understand NK cell function during pregnancy, we assessed the ability of the two main subsets of NK cells, CD56dim, and CD56bright NK cells, to respond to influenza-virus infected cells and tumor cells. During pregnancy, CD56dim and CD56bright NK cells displayed enhanced functional responses to both infected and tumor cells, with increased expression of degranulation markers and elevated frequency of NK cells producing IFN-γ. To better understand the mechanisms driving this enhanced function, we profiled CD56dim and CD56bright NK cells from pregnant and non-pregnant women using mass cytometry. NK cells from pregnant women displayed significantly increased expression of several functional and activation markers such as CD38 on both subsets and NKp46 on CD56dim NK cells. NK cells also displayed diminished expression of the chemokine receptor CXCR3 during pregnancy. Overall, these data demonstrate that functional and phenotypic shifts occur in NK cells during pregnancy that can influence the magnitude of the immune response to both infections and tumors.

Breast cancer, placenta and pregnancy.

BACKGROUND: Breast cancer is one of the most frequently diagnosed malignancies during pregnancy. Tumours often present characteristics of high malignancy and are hormone receptor negative/HER2 positive or triple negative. In general, pregnancy, including the postpartum period, is associated with a transiently increased risk of developing breast cancer but followed by a long-lasting protective period. Placental metastases are very rare and, thus far, breast cancer metastases in the foetal compartment have not been described. To discuss these apparently contradictory observations, this narrative review resumes immunological and hormonal alterations during pregnancy potentially affecting breast cancer risk as well as tumour growth and behaviour. OBSERVATIONS: Upregulation of breast cancer-associated genes involved in immunological and reproductive processes has been observed in parous women and is potentially responsible for a transiently increased risk in pregnancy. In contrast, maternal immunisation and immunoglobulin production against antigens expressed on trophoblast cells, such as specific glycosylation patterns of mucin-1 or RCAS1-associated truncated glycans, seem to prevent breast cancer development in later years. Animal and human studies indicate that T cells are involved in these processes. Several placenta-derived factors, especially kisspeptin, have direct anti-tumour effects. The pregnancy-related increase of estrogen, progesterone, and other hormones influence growth and characteristics of breast cancer while the role of further placenta-secreted factors is still controversially discussed. CONCLUSION: Several factors and cells are involved in altered breast cancer risk during and after pregnancy and have potential for developing novel treatment strategies in future.

A comparative analysis of immune privilege in pregnancy and cancer in the context of checkpoint blockade immunotherapy.

Despite their abilities to elicit immune responses, both syngeneic tumors and the half-mismatched placenta grow in the host, unlike a tissue allograft that is aggressively rejected. This is because of local and systemic factors that contribute to the immunologic privilege of tumors and the placenta. Checkpoint blockade immunotherapies subvert this privilege, with spectacularly beneficial outcomes in subsets of patients with certain types of cancer. A challenge for the community of scientists and clinicians is to replicate these successes in pregnant patients with cancer, without harm to the placenta. Here we compare and contrast the immunology of cancers and the placenta, and suggest that immunotherapy for pregnant patients with cancer may be a reasonable option, but that this should be explored systematically.

Light Chain Deposition Disease Associated With Multiple Myeloma Developing in Late Pregnancy.

Preeclampsia is the most common cause of proteinuria with hypertension during pregnancy. Primary kidney disease and kidney disease secondary to systemic disorders may rarely occur during pregnancy, resulting in proteinuria. A 34-year-old woman was admitted to our hospital with abdominal distention and lower extremity edema. The pregnancy was terminated at the 24th week of gestation due to preterm labor. Even after the delivery, proteinuria and renal deterioration continued to progress. The M-peak was not found on serum and urine protein electrophoresis. The serum free light chains assay showed absolute elevation of lambda chains at 1013.9 mg/L with a decreased kappa to lambda ratio of 0.05. Kidney biopsy revealed light chain deposition disease with lambda light chain deposits on immunofluorescence. Bone marrow examination was compatible with multiple myeloma. To our knowledge, this is the first reported case of light chain deposition disease associated with multiple myeloma during pregnancy.

Chemosensitivity, tumor infiltrating lymphocytes (TILs), and survival of postpartum PABC patients treated by neoadjuvant chemotherapy.

BACKGROUND: Pregnancy-associated breast cancer (PABC) refers to breast cancers (BC) diagnosed during pregnancy or shortly after birth. Although the inflammatory environment of post-partum PABC cases (designed as PP-PABC) may be deleterious, so far PP-PABC have scarcely been distinguished from breast cancers diagnosed during pregnancy. Furthermore, whether PP-PABC cases have an enhanced immune infiltration remains unknown. We investigated chemosensitivity, immune infiltration and survival of PP-PABC patients treated by neoadjuvant chemotherapy (NAC) compared to non-PABC matched BC patients. MATERIALS AND METHODS: We identified PP-PABC cases among a cohort of 1199 invasive BC treated with NAC between 2002 and 2012. Each PP-PABC case was matched with 3 non-PABC controls, according to age and pathological breast cancer subtype. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival (DFS) was assessed by univariate and multivariate analyses. RESULTS: Our final population study was composed of 116 patients (29 PP-PABC and 87 non-PABC). Median follow-up was of 49.0 and 29.3 months, respectively. After NAC, pCR rates (p = 0.64), post-NAC immune infiltration (stromal TILs: p = 0.67; intratumoral TILs: p = 0.14), and DFS rates (p = 0.17) were comparable between PP-PABC and non-PABC patients in global population. Similar results were found after stratification by pathological subtype. CONCLUSION: We observed similar patterns between postpartum PABC and control tumors in terms of chemosensitivity, immune infiltration, and prognostic. Our results enhance the idea that PP-PABC should receive the same standard of care treatment as other patients, including neoadjuvant chemotherapy.

The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia.

To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person-years of follow-up. Autoimmune manifestations were analyzed in 194 women with known obstetric history and known number of long-term sexual partners, and in the 389 male CLL patients for comparison. One hundred and fifty-nine of the CLL patients exhibited autoimmune manifestations, 38% in females and 21% in men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer with parietal cell autoantibodies and idiopathic thrombocytopenic purpura were equally common in women and men, whereas autoimmune thyroiditis, Sjögren's syndrome, rheumatoid arthritis and systemic lupus erythematosus were seen in higher rates in women than in men. The spectrum of autoimmunity suggests that pregnancy-related alloimmunization may be involved in the development of autoimmunity in CLL.

Protective effect of pregnancy against transplantation of lymphoma in rats.

Pregnancy was considered to aggravate concomitant neoplasia; however, recent observations in humans and experimental animals suggest that on the contrary tumor growth may be unfavorably affected by pregnancy. For this relationship to be investigated, a serially transplantable virus-induced lymphoma was inoculated into female rats of two different strains (WF and SD) in early or in late pregnancy. While all nonpregnant control rats died with lymphoma in 8-10 weeks, 36-75% of rats inoculated with lymphoma cells in the 1st week of pregnancy remained free of tumors, and 20-54% had tumors half the size of those in controls. When lymphoma cells were inoculated in the last week of pregnancy, the protective effect of pregnancy, although less clearly manifested, still resulted in 11% rats free of tumors and 78-91% rats with tumors markedly smaller than those of controls. Nonpregnant rats receiving pregnant rat serum in twice weekly injections grew tumors only 25-60% the size of those in rats receiving sera of nonpregnant rats. In vitro, pregnant rat sera added to the tissue culture media of rat lymphoma (AS line) or human leukemia (MOLT-4) cells resulted in reductions of viable target cells of 67-71%, respectively. The present experiments show that transplanted lymphoma cells that are 100% lethal in nonpregnant rats were totally or partially inhibited in their growth when the recipients were pregnant. Similar inhibiting effects were observed when pregnant rat serum was administered to lymphoma cells in vivo and in vitro. The protective effect against tumor growth was greater during early pregnancy, less accentuated during late pregnancy, and ceased entirely post partum and particularly during lactation, when tumor growth resumed on an accelerated course.

Placental immunoregulation.

Mammalian gestation is complex and varies widely among species, but the embryonic contribution to the maternal-fetal interface, the trophoblast, remains constant. Alloantigen and stage/tissue specific antigens are present on the trophoblast in low concentration and often in locations inaccessible to maternal immune effectors. Nonetheless, pregnancy does prime the mother for humoral immunity; cell-mediated responses are more difficult to demonstrate. The placenta appears to be an efficient block to cellular traffic into the fetus; the placental barrier to specific antibody has been established, but its efficiency is controversial. Nonspecific, local, active suppression mediated by lymphoid cells within the decidua is apparently an important concomitant of successful gestation. Yet there is evidence that an ongoing immune response is beneficial to pregnancy, allowing an increase in placental size in response to growth-promoting lymphokines while blocking graft-rejection mechanisms. Thus it appears that immunoregulation at the maternal-fetal interface is complex, and no single mechanism can account for the success of the "fetal allograft".

Maternal-fetal transfer of anti-N-methyl-D-aspartate receptor antibodies.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a neuroautoimmune disease commonly associated with ovarian teratomas. It is characterized by neuropsychiatric symptoms, seizures, and autonomic instability. Few cases are described in pregnancy, and little is known about potential fetal effects. CASE: Anti-NMDA receptor encephalitis was diagnosed at 24 weeks of gestation. No improvement occurred with intravenous immunoglobulin, methylprednisolone, and plasmapheresis. Imaging was unremarkable. Cesarean delivery with concurrent bilateral oophorectomy resulted in prompt maternal improvement. Antibody titers were positive in cord blood. CONCLUSION: Anti-N-methyl-D-aspartate receptor encephalitis in pregnancy can lead to NMDA receptor antibodies in the fetal circulation. Pregnancy interruption through early delivery with or without oophorectomy may accelerate maternal recovery.

Tumour infiltrating lymphocytes (TILs) in breast cancer during pregnancy.

BACKGROUND: Tumour infiltrating lymphocytes (TILs) is one of the most exciting breast cancer biomarkers, yet no data is available on its prevalence in tumours diagnosed during pregnancy. METHODS: We evaluated the prevalence of TILs (stromal and intratumoural) in pregnant and non-pregnant young breast cancer patients. RESULTS: 11/116 (9.6%) of the non-pregnant and 2/86 (2.3%) pregnant patients had TILs ≥ 50% (p < 0.001) with highest prevalence observed in triple negative tumours (p = 0.01). CONCLUSIONS: This is the first report on TILs in tumours diagnosed during pregnancy. The low prevalence could reflect the state of low host immunity associated with pregnancy.

Nodular disease during pregnancy.

The incidence of autoimmune disease of the thyroid approaches 10% in women. This autoimmune state, which predisposes to the development of thyroid neoplasia, especially in patients with subclinical hypothyroidism, combined with tumor growth and immunologic factors that occur in the pregnant state, account for the significant incidence of nodular thyroid disease in pregnancy. Thyroid carcinoma of follicular cell origin in a young woman can generally be expected to pursue a slow course with ample time for preoperative preparation and operative treatment. However, the pregnant state should be considered an exception and thyroid nodular disease with suspicious aspiration cytologic features should be managed with a certain degree of urgency. In an excellent article on the subject of pregnancy as a predisposing factor in thyroid neoplasia, Rosen and Walfish present a series of 30 patients with thyroid neoplasia arising during pregnancy. The incidence of thyroid carcinoma was 43% and the incidence of adenoma 37%, for an 80% overall incidence of neoplasia. Furthermore, during the course of the pregnancy, 20% of the patients showed marked increase in nodular growth, including a 26-year-old primiparous woman who developed a small nodule in the first trimester which proved to be cellular on needle aspiration biopsy. In spite of thyroid hormone treatment, the nodule grew markedly in the last trimester. At postpartum operation, the patient was found to have a papillary carcinoma with extensive unilateral neck and mediastinal node disease, which was clinically occult. These authors stress the importance of the operative treatment of thyroid neoplasia of pregnancy, either in the second trimester or immediately after delivery. We agree.

Immunologic studies of a horse with lymphosarcoma.

Immunological, clinical, and pathological investigations were conducted on a horse with lymphosarcoma. The immunological status was investigated by measuring the level of antibodies by single radial immunodiffusion test and the ability of lymphocytes to proliferate in response to mitogens. Multiple immunological abnormalities were noted in this horse. They were; (1) decreased IgM, IgG, and IgA levels in the serum despite hyperproteinemia; (2) increased in-vitro spontaneous lymphoproliferation which reflects augmented mitosis; (3) decreased lymphoproliferative response to T cell stimulants (e.g. Concanavalin-A (Con-A)) suggesting impaired T cell activation; (4) presence of immunosuppressive factors in serum as demonstrated by in-vitro lymphocyte culture systems. Clinical pathology findings revealed an unusual monoclonal alpha peak in the serum and morphologically abnormal lymphocytes distributed throughout the body. Serum fractionated by fast protein liquid chromatography (FPLC) revealed that the immunosuppressive factors were found in this abnormal alpha peak. The immunopathological findings in this horse are discussed.

Uterine carcinomas in mother cats after intrafetal inoculation of allogeneic tumor cells (K248 C and P).

Three out of 13 queens that had undergone injection of tumor cells from an allogeneic feline mammary carcinoma cell line through the wall of the pregnant uterus developed a carcinoma of the uterus. The possible role of immune tolerance associated with pregnancy and/or major histocompatibility complex (MHC) compatibility is discussed.