Cytokine networks are crucial aspects of tumour immunology, particularly for colorectal cancer (CRC), in which inflammation and antitumour immunity are key determinants of disease progression. In ...this Review, we highlight new insights into the functions of well-known cytokines in CRC, describe recently discovered roles for a growing number of novel players, and emphasize the complexity and therapeutic implications of the cytokine milieu. We also discuss how cancer mutations and epigenetic adaptations influence the oncogenic potential of cytokines, a relatively unexplored area that could yield crucial insights into tumour immunology and facilitate the effective application of cytokine-modulatory therapies for CRC.
Gut microbes have ascended to prominence as key modulators of host immunity, raising the possibility that they could influence the outcome of cancer immunotherapy. Two recent studies address this ...question by identifying specific gut-resident bacteria as drivers of checkpoint blockade immunotherapy in pre-clinical tumor models.
Gut microbes have ascended to prominence as key modulators of host immunity, raising the possibility that they could influence the outcome of cancer immunotherapy. Two recent studies address this question by identifying specific gut-resident bacteria as drivers of checkpoint blockade immunotherapy in pre-clinical tumor models.
Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the ...estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.
The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1.
In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.
ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.
Although costly to maintain, protein homeostasis is indispensable for normal cellular function and long-term health. In mammalian cells and tissues, daily variation in global protein synthesis has ...been observed, but its utility and consequences for proteome integrity are not fully understood. Using several different pulse-labelling strategies, here we gain direct insight into the relationship between protein synthesis and abundance proteome-wide. We show that protein degradation varies in-phase with protein synthesis, facilitating rhythms in turnover rather than abundance. This results in daily consolidation of proteome renewal whilst minimising changes in composition. Coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, particularly the ribosome, the most abundant species of complex in the cell. Daily turnover and proteasomal degradation rhythms render cells and mice more sensitive to proteotoxic stress at specific times of day, potentially contributing to daily rhythms in the efficacy of proteasomal inhibitors against cancer. Our findings suggest that circadian rhythms function to minimise the bioenergetic cost of protein homeostasis through temporal consolidation of protein turnover.
Synopsis
Protein homeostasis is costly to maintain but indispensable for normal cellular function and must be maintained in the face of daily rhythms in global protein production. Here, various pulse-labelling strategies are used to investigate the relationship between protein synthesis and abundance proteome-wide over circadian timescales.
Fraction- and time-resolved pulse-SILAC shows rhythmic degradation occurs in phase with protein synthesis at the global level, facilitating daily variation in protein turnover whilst minimising changes in protein abundance.
Global protein synthesis, degradation, and turnover is highest during the 6-8 hours following maximal production of the clock protein PER2.
Nascent ribosomes assemble with a 24-hour oscillation, peaking after the highest PER2 reporter expression, without corresponding rhythmic changes in ribosomal abundance.
The cellular and mouse organismal response to proteotoxic stress conditions varies based on the time of administration.
Protein homeostasis is maintained by daily rhythms in protein synthesis and degradation rates.
The most important clinical biomarker for breast cancer management is oestrogen receptor alpha (ERα). Tumours that express ER are candidates for endocrine therapy and are biologically less ...aggressive, while ER-negative tumours are largely treated with conventional chemotherapy and have a poor prognosis. Despite its significance, the mechanisms regulating ER expression are poorly understood. We hypothesised that the inflammatory cytokine oncostatin M (OSM) can downregulate ER expression in breast cancer. Recombinant OSM potently suppressed ER protein and mRNA expression in vitro in a dose- and time-dependent manner in two human ER+ breast cancer cell lines, MCF7 and T47D. This was dependent on the expression of OSM receptor beta (OSMRβ) and could be blocked by inhibition of the MEKK1/2 mitogen-activated protein kinases. ER loss was also necessary for maximal OSM-induced signal transduction and migratory activity. In vivo, high expression of OSM and OSMR mRNA (determined by RT-PCR) was associated with reduced ER (P<0.01) and progesterone receptor (P<0.05) protein levels in a cohort of 70 invasive breast cancers. High OSM and OSMR mRNA expression was also associated with low expression of ESR1 (ER, P<0.0001) and ER-regulated genes in a previously published breast cancer gene expression dataset (n=321 cases). In the latter cohort, high OSMR expression was associated with shorter recurrence-free and overall survival in univariate (P<0.0001) and multivariate (P=0.022) analyses. OSM signalling may be a novel factor causing suppression of ER and disease progression in breast cancer.
When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes ...to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer.
In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3)) and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1)) correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors HR: 2.314 (95% CI 1.049-5.106); p = 0.0377. Patients with high vascular endothelial growth factor (VEGF) expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors HR: 2.522 (95% CI 1.097-5.799); p = 0.0294.
Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.
Single nucleotide polymorphisms (SNPs) in the fat mass and obesity-associated (FTO) locus are associated with obesity, but lifestyle factors may modulate the obesity risk related to FTO. This study ...examined the physical activity and dietary patterns of 528 physically active white men and women (mean (SD): 34.9 (9.5) years, 26.6 (4.3) kg·m−2) carrying different risk variants of FTO SNP rs9939609. Sex, age, and anthropometric measurements (stature, body mass, and waist circumference) were self-reported using an online questionnaire, and body mass index and waist-to-height ratio were calculated. Physical activity and eating behaviour were assessed using the International Physical Activity Questionnaire (IPAQ) and Three-Factor Eating Questionnaire (TFEQ), respectively. Body mass, body mass index (BMI), waist circumference, and waist-to-height ratio were not significantly different between individuals expressing different FTO rs9939609 risk variants (all P≥0.66). The cohort was physically active (4516 (3043) total MET min·week−1), although homozygous risk allele carriers (AA) displayed higher TFEQ cognitive restraint compared with nonrisk allele carriers (TT) (ES = 0.33 and P=0.03). In conclusion, obesity-related parameters were not different in physically active individuals expressing different risk variants of FTO rs9939609, although homozygous risk allele carriers exhibited higher cognitive restraint.
It is becoming clear that inflammation-associated mechanisms can affect progression of breast cancer and modulate responses to treatment. Estrogen receptor alpha (ERα (ESR1)) is the principal ...biomarker and therapeutic target for endocrine therapies in breast cancer. Over 70% of patients are ESR1-positive at diagnosis and are candidates for endocrine therapy. However, ESR1-positive tumours can become resistant to endocrine therapy. Multiple mechanisms of endocrine resistance have been proposed, including suppression of ESR1. This review discusses the relationship between intratumoural inflammation and endocrine resistance with a particular focus on inflammation-mediated suppression of ESR1.
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