ABSTRACT
Most biologists know of the interferons IFNα, IFNß, and IFNγ and their roles in immunity and infection, but they may not have heard of IFNε. A recent study in Nature suggests that IFNε can act as a tumor suppressor in serous ovarian cancers.
Subject(s)
Interferons , Ovarian Neoplasms , Female , Humans , Ovarian Neoplasms/immunology , Interferons/metabolismABSTRACT
Studies of the high-grade serous ovarian cancer (HGSOC) tumor microenvironment, the most lethal gynecological cancer, aim to enhance the efficiency of established therapies. Cell motility is an important process of anti-tumor response. Using ex vivo human and mouse HGSOC tumor slices combined with time-lapse imaging, we assessed the motility of CD8+ T and myeloid cells. We developed a semi-supervised analysis of cell movements, identifying four cell behaviors: migrating, long migrating, static, and wobbling. Tumor slices were maintained 24h ex vivo, retaining viability and cell movements. Ex vivo treatments with lipopolysaccharide altered CD8+ T and myeloid cell behavior. In vivo chemotherapy reduced ex vivo cell movements in human and mouse tumors and differentially affected CD8+ T and myeloid cells in chemo-sensitive and chemo-resistant mouse models. Ex vivo tumor slices can extend in vivo mouse studies to human, providing a stepping stone to translate mouse cancer studies to clinical trials.
ABSTRACT
Neoadjuvant chemotherapy (NACT) may stimulate anticancer adaptive immune responses in high-grade serous ovarian cancer (HGSOC), but little is known about effects on innate immunity. Using omental biopsies from HGSOC, and omental tumors from orthotopic mouse HGSOC models that replicate the human tumor microenvironment, we studied the impact of platinum-based NACT on tumor-associated macrophages (TAM). We found that chemotherapy reduces markers associated with alternative macrophage activation while increasing expression of proinflammatory pathways, with evidence of inflammasome activation. Further evidence of a shift in TAM functions came from macrophage depletion via CSF1R inhibitors (CSF1Ri) in the mouse models. Although macrophage depletion in established disease had no impact on tumor weight or survival, CSF1Ri treatment after chemotherapy significantly decreased disease-free and overall survival. This decrease in survival was accompanied by significant inhibition of adaptive immune response pathways in the tumors. We conclude that chemotherapy skews the TAM population in HSGOC toward an antitumor phenotype that may aid adaptive immune responses, and therapies that enhance or sustain this during remission may delay relapse.
Subject(s)
Cystadenocarcinoma, Serous/immunology , Ovarian Neoplasms/immunology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Tumor-Associated Macrophages/immunology , Adaptive Immunity , Animals , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/mortality , Cystadenocarcinoma, Serous/pathology , Disease Models, Animal , Disease-Free Survival , Female , Humans , Immunity, Innate , Mice , Mice, Inbred C57BL , Neoadjuvant Therapy/methods , Neoplasm Grading , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Tumor Microenvironment/immunologySubject(s)
Tuberculosis, Female Genital/diagnosis , Aged , Antibiotics, Antitubercular/therapeutic use , Diagnosis, Differential , Female , Humans , Hysterectomy , Mycobacterium tuberculosis/isolation & purification , Polymerase Chain Reaction , Postmenopause , Pyometra/etiology , Salpingo-oophorectomy , Tomography, X-Ray Computed , Tuberculosis, Female Genital/therapy , Uterus/diagnostic imaging , White PeopleABSTRACT
Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.
