Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

Regulatory T Cells

The role of extracellular vesicles in cancer

Targeting replication stress in cancer therapy

High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research. 

/pdf/ovarian-cancer-mutational-processes-drive-site-specific-11a0ymty.pdf

Ovarian cancer mutational processes drive site-specific immune evasion

Cisplatin is one of the most effective chemotherapy drugs for ovarian cancer, but resistance is common. The initial response to platinum-based chemotherapy is as high as 80%, but in most advanced patients, final relapse and death are caused by acquired drug resistance. The development of resistance to therapy in ovarian cancer is a significant hindrance to therapeutic efficacy. The resistance of ovarian cancer cells to chemotherapeutic mechanisms is rather complex and includes multidrug resistance, DNA damage repair, cell metabolism, oxidative stress, cell cycle regulation, cancer stem cells, immunity, apoptotic pathways, autophagy and abnormal signaling pathways. The present review provided an update of recent developments in our understanding of the mechanisms of ovarian cancer platinum-based chemotherapy resistance, discussed current and emerging approaches for targeting these patients and presented challenges associated with these approaches, with a focus on development and overcoming resistance.

/pdf/molecular-mechanisms-of-platinum-based-chemotherapy-1pmzqlpg.pdf

Molecular mechanisms of platinum-based chemotherapy resistance in ovarian cancer

Despite advances in immuno-oncology, the relationship between tumor genotypes and response to immunotherapy remains poorly understood, particularly in high-grade serous tubo-ovarian carcinomas (HGSC). We developed a series of mouse models that carry genotypes of human HGSCs and grow in syngeneic immunocompetent hosts to address this gap. We transformed murine-fallopian tube epithelial cells to phenocopy homologous recombination–deficient tumors through a combined loss of Trp53, Brca1, Pten, and Nf1 and overexpression of Myc and Trp53R172H, which was contrasted with an identical model carrying wild-type Brca1. For homologous recombination–proficient tumors, we constructed genotypes combining loss of Trp53 and overexpression of Ccne1, Akt2, and Trp53R172H, and driven by KRASG12V or Brd4 or Smarca4 overexpression. These lines form tumors recapitulating human disease, including genotype-driven responses to treatment, and enabled us to identify follistatin as a driver of resistance to checkpoint inhibitors. These data provide proof of concept that our models can identify new immunotherapy targets in HGSC. Significance: We engineered a panel of murine fallopian tube epithelial cells bearing mutations typical of HGSC and capable of forming tumors in syngeneic immunocompetent hosts. These models recapitulate tumor microenvironments and drug responses characteristic of human disease. In a Ccne1-overexpressing model, immune-checkpoint resistance was driven by follistatin. This article is highlighted in the In This Issue feature, p. 211

/pdf/genetically-defined-syngeneic-mouse-models-of-ovarian-cancer-4keu2bahw0.pdf

Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy.

Many human cancers manifest the capability to circumvent attack by the adaptive immune system. In this work, we identified a component of immune evasion that involves frequent up-regulation of fragile X mental retardation protein (FMRP) in solid tumors. FMRP represses immune attack, as revealed by cancer cells engineered to lack its expression. FMRP-deficient tumors were infiltrated by activated T cells that impaired tumor growth and enhanced survival in mice. Mechanistically, FMRP’s immunosuppression was multifactorial, involving repression of the chemoattractant C-C motif chemokine ligand 7 (CCL7) concomitant with up-regulation of three immunomodulators—interleukin-33 (IL-33), tumor-secreted protein S (PROS1), and extracellular vesicles. Gene signatures associate FMRP’s cancer network with poor prognosis and response to therapy in cancer patients. Collectively, FMRP is implicated as a regulator that orchestrates a multifaceted barrier to antitumor immune responses. Description FMRP and tumor immunity Many tumors have developed mechanisms rendering them resistant to attack and destruction by the immune system. Zeng et al. report that fragile X mental retardation protein (FMRP) is highly expressed in human cancers, and they propose that it is involved in antitumor immunity. FMRP is best known as an RNA-binding protein that regulates the stability and translation of neuronal RNAs. By genetically inactivating the FMRP gene in mouse cancer cells, the researchers found that FMRP-deficient tumors had reduced growth and were more susceptible to attack by T lymphocytes. Tumor cells lacking FMRP showed remodeling of the tumor microenvironment, macrophage polarization, and upregulation of the chemokines involved in effector CD8+ T cell recruitment. —PNK Genetic inactivation of the neuronal fragile X mental retardation protein increased CD8+ T cell infiltration and reduced the growth of mouse tumors. INTRODUCTION Cancer biology and therapy have been transformed by knowledge about immunoregulatory mechanisms that govern adaptive immunity. Although some forms of treatment resistance are related to the intentionally transitory operations of the adaptive immune system, others reflect more subtle requirements to modulate the immune system in different contexts. In this work, we identified an immunoregulatory mechanism involving the neuronal RNA binding protein fragile X mental retardation protein (FMRP), which broadly regulates protein translation and mRNA stability and is aberrantly up-regulated in multiple forms of cancer. RATIONALE This study was motivated by reports that cancer cells naturally overexpressing FMRP, whose loss of expression in developing neurons causes cognitive defects, were invasive and metastatic. We investigated the expression of FMRP in human tumors, further assessed its tumor-promoting functions in mouse models of cancer, and evaluated its association with prognosis for human cancer patients. RESULTS When human tumor tissue microarrays were immunostained for expression of FMRP, a majority of tumors expressed FMRP, whereas cognate normal tissues did not. To investigate the functional significance of this broad up-regulation, the FMR1 gene was ablated through CRISPR-Cas9 gene editing (FMRP-KO, where KO indicates knockout) in mouse cancer cell lines that were inoculated into both immunodeficient and syngeneic immunocompetent mice to establish tumors in parallel with wild-type (WT) FMRP-expressing cell lines. Mice bearing FMRP-KO tumors had similar survival compared with isogenic WT tumors in immunodeficient hosts, indicating that FMRP was not involved in stimulating tumor growth per se. By contrast, tumor growth was impaired and survival extended in immunocompetent hosts, implicating the adaptive immune system. Indeed, FMRP-expressing WT tumors were largely devoid of T cells, whereas FMRP-KO tumors were highly inflamed. Depletion of CD8 and CD4 T cells restored tumor growth and reduced survival, implicating FMRP in immune evasion in WT tumors. WT and FMRP-KO tumors were profiled by single-cell RNA sequencing, revealing marked differences in genome-wide transcription and abundance of cancer cells, macrophages, and T cells. To elucidate the effects of this multifaceted regulatory protein, we performed several functional perturbations, revealing that: FMRP-expressing cancer cells produce the chemokine interleukin-33 (IL-33), which induces regulatory T cells, as well as tumor-secreted protein S (PROS1) ligand and exosomes that elicit tumor-promoting (M2) macrophages. Both cell types are immunosuppressive, collectively contributing to the barrier against T cell attack. By contrast, FMRP-KO cancer cells down-regulate all three factors and up-regulate C-C motif chemokine ligand 7 (CCL7), which helps recruit and activate T cells. Additionally, immunostimulatory macrophages develop in this context that express three proinflammatory chemokines—CCL5, CXCL9, and CXCL10—which cooperate with CCL7 in recruiting T cells. Finally, neither FMR1 mRNA nor FMRP protein levels were sufficient to predict outcomes in cohorts of cancer patients. Recognizing FMRP’s function as an RNA binding protein that modulates mRNA stability and hence levels in transcriptome datasets, a gene signature reflecting FMRP’s cancer regulatory activity (involving 156 genes) was developed by comparing FMRP-expressing versus FMRP-deficient cancer cells, both in culture and within tumors. Our FMRP cancer activity signature was prognostic for survival across multiple human cancers; anticorrelated with the intensity of T cell infiltration in different tumor types, consistent with FMRP’s immunosuppressive effects; and was associated with comparatively poor responses to immune checkpoint inhibitors and immune-dependent chemotherapy in selected cohorts. CONCLUSION FMRP is revealed as a regulator of a network of genes and cells in the tumor microenvironment that contribute to the capability of tumors to evade immune destruction. FMRP enables tumors to evade being attacked by the immune system. Up-regulated FMRP expression and activity are involved in an immunosuppressive program in cancer cells (upper left) that renders tumors impenetrable, creating so-called immune deserts (upper right). By contrast, its absence is associated with a reprogrammed tumor microenvironment that recruits and activates T lymphocytes, producing inflamed tumors, including CD8 T cells (red immunostain; lower right) with consequently beneficial immune destruction. Tregs, regulatory (immunosuppressive) T cells.

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

Connexins (Cx) are primary components of gap junctions that selectively allow molecules to be exchanged between adjacent cells, regulating multiple cellular functions. Along with their channel forming functions, connexins play a variety of roles in different stages of tumorigenesis and their roles in tumor initiation and progression is isoform- and tissue-specific. While Cx26 and Cx43 were downregulated during breast tumorigenesis, Cx32 was accumulated in the cytoplasm of the cells in lymph node metastasis of breast cancers and Cx32 was further upregulated in metastasis. Cx32's effect on cell proliferation, gap junctional communication, hemichannel activity, cellular motility and epithelial-to-mesenchymal transition (EMT) were investigated by overexpressing Cx32 in Hs578T and MCF7 breast cancer cells. Additionally, the expression and localization of Cx26 and Cx43 upon Cx32 overexpression were examined by Western blot and immunostaining experiments, respectively. We observed that MCF7 cells had endogenous Cx32 while Hs578T cells did not and when Cx32 was overexpressed in these cells, it caused a significant increase in the percentages of Hs578T cells at the S phase in addition to increasing their proliferation. Further, while Cx32 overexpression did not induce hemichannel activity in either cell, it decreased gap junctional communication between Hs578T cells. Additionally, Cx32 was mainly observed in the cytoplasm in both cells, where it did not form gap junction plaques but Cx32 overexpression reduced Cx43 levels without affecting Cx26. Moreover, migration and invasion potentials of Hs578T and migration in MCF7 were reduced upon Cx32 overexpression. Finally, the protein level of mesenchymal marker N-cadherin decreased while epithelial marker ZO-1 and E-cadherin increased in Hs578T cells. We observed that Cx32 overexpression altered cell proliferation, communication, migration and EMT in Hs578T, suggesting a tumor suppressor role in these cells while it had minor effects on MCF7 cells. 

Connexin 32 overexpression increases proliferation, reduces gap junctional intercellular communication, motility and epithelial-to-mesenchymal transition in Hs578T breast cancer cells

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Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of Combination Immunotherapy.

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

Connexin 32 overexpression increases proliferation, reduces gap junctional intercellular communication, motility and epithelial-to-mesenchymal transition in Hs578T breast cancer cells