Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that ...reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1
CD8
T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8
T cells. Furthermore, an increase in the frequency of the CX3CR1
subset in circulating CD8
T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.
Abstract Background We evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network ...(USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function. Methods Overall and site-specific cancer incidence rates were evaluated in subjects with PIDD (n = 3,658) enrolled in the USIDNET registry from 2003-2015, and compared with age-adjusted incidence rates in the SEER database. Results We observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared to the age-adjusted SEER population (p<0.001). Men with PIDD had a 1.91-fold excess relative risk of cancer compared to the age-adjusted male population (p<0.001), while women with PIDD had similar overall cancer rates compared to the age-adjusted female population. Of the four most common malignancies in men and women in SEER (lung, colon, breast, and prostate cancers), we found no significant increase in these diagnoses in subjects with PIDD. Significant increases in lymphoma in both men (10-fold increase, p<0.001) and women (8.34-fold increase, p<0.001) with PIDD were observed. Conclusions Excess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Tumor-associated or -infiltrating lymphocytes (TALs or TILs) co-express multiple immune inhibitory receptors that contribute to immune suppression in the ovarian tumor microenvironment (TME). Dual ...blockade of PD-1 along with LAG-3 or CTLA-4 has been shown to synergistically enhance T-cell effector function, resulting in a delay in murine ovarian tumor growth. However, the mechanisms underlying this synergy and the relative contribution of other inhibitory receptors to immune suppression in the ovarian TME are unknown. Here, we report that multiple immune checkpoints are expressed in TALs and TILs isolated from ovarian tumor-bearing mice. Importantly, blockade of PD-1, LAG-3, or CTLA-4 alone using genetic ablation or blocking antibodies conferred a compensatory upregulation of the other checkpoint pathways, potentiating their capacity for local T-cell suppression that, in turn, could be overcome through combinatorial blockade strategies. Whereas single-agent blockade led to tumor outgrowth in all animals, dual antibody blockade against PD-1/CTLA-4 or triple blockade against PD-1/LAG-3/CTLA-4 resulted in tumor-free survival in 20% of treated mice. In contrast, dual blockade of LAG-3 and CTLA-4 pathways using PD-1 knockout mice led to tumor-free survival in 40% of treated mice, suggesting a hierarchical ordering of checkpoint function. Durable antitumor immunity was most strongly associated with increased numbers of CD8
+
T cells, the frequency of cytokine-producing effector T cells, reduced frequency of Tregs and arginine-expressing monocytic myeloid-derived suppressor cells in the peritoneal TME. These data provide a basis for combinatorial checkpoint blockade in clinical intervention for ovarian cancer.
Cells with sphere forming capacity, spheroid cells, are present in the malignant ascites of patients with epithelial ovarian cancer (EOC) and represent a significant impediment to efficacious ...treatment due to their putative role in progression, metastasis and chemotherapy resistance. The exact mechanisms that underlie EOC metastasis and drug resistance are not clear. Understanding the biology of sphere forming cells may contribute to the identification of novel therapeutic opportunities for metastatic EOC. Here we generated spheroid cells from human ovarian cancer cell lines and primary ovarian cancer. Xenoengraftment of as few as 2000 dissociated spheroid cells into immune-deficient mice allowed full recapitulation of the original tumor, whereas >10(5) parent tumor cells remained non-tumorigenic. The spheroid cells were found to be enriched for cells with cancer stem cell-like characteristics such as upregulation of stem cell genes, self-renewal, high proliferative and differentiation potential, and high aldehyde dehydrogenase (ALDH) activity. Furthermore, spheroid cells were more aggressive in growth, migration, invasion, scratch recovery, clonogenic survival, anchorage-independent growth, and more resistant to chemotherapy in vitro. (13)C-glucose metabolic studies revealed that spheroid cells route glucose predominantly to anaerobic glycolysis and pentose cycle to the detriment of re-routing glucose for anabolic purposes. These metabolic properties of sphere forming cells appear to confer increased resistance to apoptosis and contribute to more aggressive tumor growth. Collectively, we demonstrated that spheroid cells with cancer stem cell-like characteristics contributed to tumor generation, progression and chemotherapy resistance. This study provides insight into the relationship between tumor dissemination and metabolic attributes of human cancer stem cells and has clinical implications for cancer therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antibodies to PD-1 protein and to one of its ligands, PD-L1, have shown antitumor activity. Unleashing T cells from inhibitory signals may be a strategy to treat cancers. Autoimmune side effects from ...anti–PD-L1 antibody seem less severe than those from anti–CTLA-4 antibody.
Passive cancer immunotherapy that uses tumor-targeted monoclonal antibodies has achieved broad therapeutic efficacy.
1
However, T-cell directed immunotherapy has been less successful.
2
Despite the large number of tumor antigens induced by genetic and epigenetic changes found in all cancers, tumors resist immune attack by inducing tolerance among tumor-specific T cells and by expressing ligands that engage inhibitory receptors and dampen T-cell functions within the tumor microenvironment.
3
Preclinical and clinical data show that antibody blockade of these immune checkpoints can significantly enhance antitumor immunity.
4
Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), an inhibitory receptor that down-modulates the initial stages of T-cell activation, was the . . .
NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo ...tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8⁺ T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8⁺ T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8⁺ T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8⁺ T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8⁺LAG-3⁺PD-1⁺ T cells were more impaired in IFN-γ/TNF-α production compared with LAG-3⁺PD-1⁻ or LAG-3⁻PD-1⁻ subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8⁺ T cells, indicating that antitumor function of NY-ESO-1-specific CD8⁺ T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Adoptive cell therapy (ACT) is one of promising immunotherapies for cancer patients by providing a large amount of cancer antigen-specific effector T cells that can be manufactured rapidly by ex vivo ...gene engineering. To provide antigen-specificity to patients' autologous T cells in a short-term culture, T-cell receptors (TCRs) or chimeric antigen receptors (CARs) are transduced to bulk T cells. Because of intra- and inter-tumoral heterogeneity in tumor antigen expression, a repertoire of TCR or CAR genes targeting a wide range of tumor antigens are required for a broad and effective treatment by ACT. Here, we characterized immunogenicity of claudin 6 (CLDN6) in ovarian cancer patients and identified specific TCR genes from CD8
+
and CD4
+
T cells. CLDN6 protein was frequently expressed on EpCAM
+
ovarian cancer cells but not CD45
+
lymphocytes in tumor ascites of ovarian cancer patients. Spontaneous CLDN6-specific CD4
+
and CD8
+
T-cell response was detected in peripheral blood mononuclear cells (PBMCs) from 1 out of 17 ovarian cancer patients. HLA-A*02:01 (A2) and DR*04:04 (DR4)-restricted TCR genes were isolated from CLDN6-specific CD8
+
and CD4
+
T cells, respectively. T cells that were engineered with A2-restricted TCR gene recognized and killed A2
+
CLDN6
+
cancer cells. DR4-restricted TCR-transduced T cells directly recognized DR4
+
CLDN6
+
-overexpressed cancer cells. Our results demonstrate that these CLDN6-specific TCR genes are useful as therapeutic genes for ACT to patients with ovarian and other solid tumors expressing CLDN6.
Altered lipid metabolism has emerged as an important feature of ovarian cancer (OC), yet the translational potential of lipid metabolites to aid in diagnosis and triage remains unproven. We conducted ...a multi-level interrogation of lipid metabolic phenotypes in patients with adnexal masses, integrating quantitative lipidomics profiling of plasma and ascites with publicly-available tumor transcriptome data. Using Sciex Lipidyzer, we assessed concentrations of > 500 plasma lipids in two patient cohorts-(i) a pilot set of 100 women with OC (50) or benign tumor (50), and (ii) an independent set of 118 women with malignant (60) or benign (58) adnexal mass. 249 lipid species and several lipid classes were significantly reduced in cases versus controls in both cohorts (FDR < 0.05). 23 metabolites-triacylglycerols, phosphatidylcholines, cholesterol esters-were validated at Bonferroni significance (P < 9.16 × 10
). Certain lipids exhibited greater alterations in early- (diacylglycerols) or late-stage (lysophospholipids) cases, and multiple lipids in plasma and ascites were positively correlated. Lipoprotein receptor gene expression differed markedly in OC versus benign tumors. Importantly, several plasma lipid species, such as DAG(16:1/18:1), improved the accuracy of CA125 in differentiating early-stage OC cases from benign controls, and conferred a 15-20% increase in specificity at 90% sensitivity in multivariate models adjusted for age and BMI. This study provides novel insight into systemic and local lipid metabolic differences between OC and benign disease, further implicating altered lipid uptake in OC biology, and advancing plasma lipid metabolites as a complementary class of circulating biomarkers for OC diagnosis and triage.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the ...most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show that
is co-amplified and co-expressed with
, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress response. We demonstrate that
and
are head-to-head (i.e., bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOXM1 and RHNO1 each promote oncogenic phenotypes in HGSC cells, including clonogenic growth, DNA homologous recombination repair, and poly-ADP ribosylase inhibitor resistance. FOXM1 and RHNO1 are one of the first examples of oncogenic BDG, and therapeutic targeting of FOXM1/RHNO1 BDG is a potential therapeutic approach for ovarian and other cancers.
The aim of this study was to estimate the contribution of deleterious mutations in the RAD51B, RAD51C, and RAD51D genes to invasive epithelial ovarian cancer (EOC) in the population and in a ...screening trial of individuals at high risk of ovarian cancer.
The coding sequence and splice site boundaries of the three RAD51 genes were sequenced and analyzed in germline DNA from a case-control study of 3,429 patients with invasive EOC and 2,772 controls as well as in 2,000 unaffected women who were BRCA1/BRCA2 negative from the United Kingdom Familial Ovarian Cancer Screening Study (UK_FOCSS) after quality-control analysis.
In the case-control study, we identified predicted deleterious mutations in 28 EOC cases (0.82%) compared with three controls (0.11%; P < .001). Mutations in EOC cases were more frequent in RAD51C (14 occurrences, 0.41%) and RAD51D (12 occurrences, 0.35%) than in RAD51B (two occurrences, 0.06%). RAD51C mutations were associated with an odds ratio of 5.2 (95% CI, 1.1 to 24; P = .035), and RAD51D mutations conferred an odds ratio of 12 (95% CI, 1.5 to 90; P = .019). We identified 13 RAD51 mutations (0.65%) in unaffected UK_FOCSS participants (RAD51C, n = 7; RAD51D, n = 5; and RAD51B, n = 1), which was a significantly greater rate than in controls (P < .001); furthermore, RAD51 mutation carriers were more likely than noncarriers to have a family history of ovarian cancer (P < .001).
These results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of EOC that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.
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