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Cell Reports Oct 2021Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2 tumor-associated...
Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2 tumor-associated macrophages (TAMs) as being correlated with exhausted CD8 tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8 TIL infiltration and effector function. TREM2 TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.
Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Coculture Techniques; Drug Resistance, Neoplasm; Female; HEK293 Cells; Humans; Immune Checkpoint Inhibitors; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Membrane Glycoproteins; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasms; Programmed Cell Death 1 Receptor; Receptors, Immunologic; Signal Transduction; Tumor Cells, Cultured; Tumor Microenvironment; Tumor-Associated Macrophages; Mice
PubMed: 34686340
DOI: 10.1016/j.celrep.2021.109844 -
Journal of Assisted Reproduction and... Jan 2022Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent... (Review)
Review
PURPOSE
Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent literature in both humans and animals suggest that intraovarian PRP administration in the setting of poor ovarian reserve may help ovarian function and increase the chances of pregnancy.
METHODS
A comprehensive literature search through PubMed, MEDLINE databases, and recent abstracts published at relevant society meetings was performed and resulted in 25 articles and 2 abstracts published that studied effect of PRP on the ovaries for the purpose of reproduction.
RESULTS
This review article presents all the data published to date pertaining to intraovarian PRP injection and pregnancy, both naturally and after in vitro fertilization. It also presents the most recent data on the use of ovarian PRP in in vitro and animal model studies highlighting the possible mechanisms by which PRP could impact ovarian function.
CONCLUSIONS
Even though recent commentaries questioned the use of PRP as an "add-on" therapy in fertility treatment because it has not been thoroughly studied, the recent basic science studies presented here could increase awareness for considering more serious research into the efficacy of PRP as an adjunct for women with poor ovarian reserve, premature ovarian insufficiency, and even early menopause who are trying to conceive using their own oocytes. Given its low-risk profile, the hypothetical benefit of PRP treatment needs to be studied with larger randomized controlled trials.
Topics: Adult; Drug Administration Routes; Female; Humans; Ovary; Ovulation Induction; Platelet-Rich Plasma
PubMed: 35175511
DOI: 10.1007/s10815-021-02385-w -
Journal of Assisted Reproduction and... May 2021Platelet-rich plasma (PRP) has become a novel treatment in various aspects of medicine including orthopedics, cardiothoracic surgery, plastic surgery, dermatology,... (Review)
Review
PURPOSE
Platelet-rich plasma (PRP) has become a novel treatment in various aspects of medicine including orthopedics, cardiothoracic surgery, plastic surgery, dermatology, dentistry, and diabetic wound healing. PRP is now starting to become an area of interest in reproductive medicine more specifically focusing on infertility. Poor ovarian reserve, menopause, premature ovarian failure, and thin endometrium have been the main areas of research. The aim of this article is to review the existing literature on the effects of autologous PRP in reproductive medicine providing a summation of the current studies and assessing the need for additional research.
METHODS
A literature search is performed using PubMed, MEDLINE, and CINAHL Plus to identify studies focusing on the use of PRP therapy in reproductive medicine. Articles were divided into 3 categories: PRP in thin lining, PRP in poor ovarian reserve, and PRP in recurrent implantation failure.
RESULTS
In women with thin endometrium, the literature shows an increase in endometrial thickness and increase in chemical and clinical pregnancy rates following autologous PRP therapy. In women with poor ovarian reserve, autologous intraovarian PRP therapy increased anti-Mullerian hormone (AMH) levels and decreased follicle-stimulating hormone (FSH), with a trend toward increasing clinical and live birth rates. This trend was also noted in women with recurrent implantation failure.
CONCLUSIONS
Limited literature shows promise in increasing endometrial thickness, increasing AMH, and decreasing FSH levels, as well as increasing chemical and clinical pregnancy rates. The lack of standardization of PRP preparation along with the lack of large randomized controlled trials needs to be addressed in future studies. Until definitive large RCTs are available, PRP use should be considered experimental.
Topics: Anti-Mullerian Hormone; Female; Fertilization in Vitro; Humans; Infertility, Female; Ovarian Reserve; Ovulation Induction; Platelet-Rich Plasma; Pregnancy; Reproductive Medicine
PubMed: 33723748
DOI: 10.1007/s10815-021-02146-9 -
International Journal of Environmental... Apr 2022Regenerative medicine combines elements of tissue engineering and molecular biology aiming to support the regeneration and repair processes of damaged tissues, cells and... (Review)
Review
Regenerative medicine combines elements of tissue engineering and molecular biology aiming to support the regeneration and repair processes of damaged tissues, cells and organs. The most commonly used preparation in regenerative medicine is platelet rich plasma (PRP) containing numerous growth factors present in platelet granularities. This therapy is increasingly used in various fields of medicine. This article is a review of literature on the use of PRP in gynecology and obstetrics. There is no doubt that the released growth factors and proteins have a beneficial effect on wound healing and regeneration processes. So far, its widest application is in reproductive medicine, especially in cases of thin endometrium, Asherman's syndrome, or premature ovarian failure (POF) but also in wound healing and lower urinary tract symptoms (LUTS), such as urinary incontinence or recurrent genitourinary fistula auxiliary treatment. Further research is, however, needed to confirm the effectiveness and the possibility of its application in many other disorders.
Topics: Endometrium; Female; Gynecology; Humans; Platelet-Rich Plasma; Pregnancy; Regenerative Medicine; Tissue Engineering
PubMed: 35564681
DOI: 10.3390/ijerph19095284 -
Reproductive Biology and Endocrinology... Feb 2022Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems.... (Review)
Review
Primary ovarian insufficiency (POI) is a rare gynecological condition. This disease causes menstrual disturbances, infertility, and various health problems. Historically, hormone replacement therapy is the first-line treatment for this disorder. Women diagnosed with POI are left with limited therapeutic options. In order to remedy this situation, a new generation of therapeutic approaches, such as in vitro activation, mitochondrial activation technique, stem cell and exosomes therapy, biomaterials strategies, and platelet-rich plasma intra-ovarian infusion, is being developed. However, these emerging therapies are yet in the experimental stage and require precise design components to accelerate their conversion into clinical treatments. Thus, each medical practitioner bears responsibility for selecting suitable therapies for individual patients. In this article, we provide a timely analysis of the therapeutic strategies that are available for POI patients and discuss the prospects of POI therapy.
Topics: Female; Hormone Replacement Therapy; Humans; Platelet-Rich Plasma; Primary Ovarian Insufficiency; Therapies, Investigational
PubMed: 35120535
DOI: 10.1186/s12958-022-00892-8 -
Cancer Cell Jun 2019We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8 T cell infiltration in...
We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8 T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.
Topics: Animals; Antineoplastic Agents, Immunological; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Chemokine CCL5; Chemokine CXCL9; Chemotaxis, Leukocyte; Coculture Techniques; Cytokines; DNA Methylation; Dendritic Cells; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Interferon-gamma; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Macrophages; Mice, Inbred C57BL; Ovarian Neoplasms; Paracrine Communication; Receptors, CXCR3; Signal Transduction
PubMed: 31185212
DOI: 10.1016/j.ccell.2019.05.004 -
Nature Cancer Aug 2023Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC...
Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8 T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived ontogeny, whereas macrophages in ascites were more of embryonic origin. Furthermore, we characterized MAIT and dendritic cells in malignant ascites, as well as two endothelial subsets in primary tumors as predictive biomarkers for platinum-based chemotherapy response. Taken together, our study provides a global view of the female malignant ascites ecosystem and offers valuable insights for its connection with tumor tissues and paves the way for potential markers of efficacy evaluation and therapy resistance in OC.
Topics: Female; Humans; Ascites; CD8-Positive T-Lymphocytes; Ecosystem; Ovarian Neoplasms; Single-Cell Analysis
PubMed: 37488416
DOI: 10.1038/s43018-023-00599-8 -
Cancer Discovery Jan 2022Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes...
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4 and CD8 T cells. LDRT elicited predominantly CD4 cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4 cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4 effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors..
Topics: Adaptive Immunity; Adenocarcinoma, Papillary; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Disease Models, Animal; Female; Humans; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred C57BL; Ovarian Neoplasms; Radiotherapy Dosage; Tumor Microenvironment
PubMed: 34479871
DOI: 10.1158/2159-8290.CD-21-0003 -
Cancer Cell May 2022Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of...
Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3CD8CD103CD69 TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1) tissue-resident T cells (TRM cells), but not recirculating TCF1 T cells, predict ovarian cancer outcome. TRM cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on ∼13% of CD8 tumor-infiltrating T cells (∼3% of CD8 clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.
Topics: CD8-Positive T-Lymphocytes; Female; Humans; Immunologic Memory; Lymphocytes, Tumor-Infiltrating; Memory T Cells; Ovarian Neoplasms
PubMed: 35427494
DOI: 10.1016/j.ccell.2022.03.008 -
Cells Jun 2022Endometriosis is a chronic disease that affects about 10% of women of reproductive age. It can contribute to pelvic pain, infertility or other conditions such as asthma,... (Review)
Review
Endometriosis is a chronic disease that affects about 10% of women of reproductive age. It can contribute to pelvic pain, infertility or other conditions such as asthma, cardiovascular disease, breast or ovarian cancer. Research has shown that one of the conditions for the development of endometrial lesions is the dysfunction of the immune system. It appears that immune cells, such as neutrophils, macrophages, NK cells and dendritic cells, may play a specific role in the angiogenesis, growth and invasion of endometriosis cells. Immune cells secrete cytokines and defensins that also affect the endometriosis environment. This review discusses the various components of the immune system that are involved in the formation of endometrial lesions in women.
Topics: Cytokines; Endometriosis; Female; Humans; Killer Cells, Natural; Macrophages; Neutrophils
PubMed: 35805112
DOI: 10.3390/cells11132028