‘It is still coming from the centre and coming out’:The material conditions adding to over‐bureaucratised patient and public involvement for commissioning health and care in England

Abstract Objective To understand how materiality affects patient and public involvement (PPI) for commissioning and leading health and care services in the English National Health Service (NHS) context. Context From April 2013 groups of general practitioners (GPs) became members of NHS clinical commissioning groups (CCGs) to assess needs and procure core health services for and with local communities. Since July 2022, integrated care systems (ICSs) have subsumed this responsibility. NHS reorganisations have been driven by the promise of more effective and efficient health care and have led to a long history of PPI on economic, political, and moral grounds. Few studies researching PPI in clinical commissioning exist and fewer still have explored a more agentic understanding of materiality and its impact on PPI. Study Design A focused ethnography was used to examine PPI for clinical commissioning within two CCG case study sites in England. Three CCG Governing Body lay representatives, nine GP commissioners and seven service user representatives took part in focus groups and/or were interviewed. Fifteen nonparticipant observations were also carried out at CCG meetings and the associated materiality was examined. Findings The materiality of activities involved in clinical commissioning influences and shapes the nature of PPI. These forms of materiality may dilute and subvert meaningful engagement and involvement that relies on trust, leadership, learning, and partnership working. Conclusion System leaders in ICSs should consider the significance of materiality in centrally driven processes involved in PPI commissioning to reduce barriers and ensure meaningful partnerships within local communities. Patient and Public Contribution The study design ensured PPI throughout the research process in keeping with contemporary research practice guidance. The project steering committee included service users with current or recent PPI clinical commissioning experience outside of the study sites. There was PPI involvement in the original study proposal and its development including the bid for doctoral funds on which this study is based. All were involved in assessing the rigour of the data collection, interpretation of the findings and ensuring the project remained true to the aims of the study. Two members have also participated in presentation of the study findings

Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival

The expression of the immunomodulating enzyme indoleamine-2,3-dioxygenase (IDO) suppresses T-lymphocyte function, thus correlating with poor survival in a variety of cancer patients. IDO degrades the essential amino acid tryptophan leading to immunosuppressive kynurenines production. In the present study, concentrations of tryptophan, 3-hydroxykynurenine, and kynurenine were measured in pre-treatment serum samples of 251 cervical cancer patients by a mass-spectrometric method (XLC-MS/MS) and IDO activity determined by the kynurenine/tryptophan (Kyn/Trp) ratio. A low concentration of tryptophan was found to be significantly associated with tumors greater than 4 cm and lymph node metastatic spread. Furthermore, significant positive correlations were found between high concentrations of the tryptophan metabolites kynurenine and 3-hydroxykynurenine and advanced disease stage (FIGO > IIA) and lymph node metastases. High levels of kynurenine were further associated with parametrial invasion and tumor size. A high Kyn/Trp ratio was related to lymph node metastasis, FIGO stage, tumor size, parametrial invasion and poor disease-specific survival. These results suggest that IDO activation is linked to poor clinicopathological parameters and worse survival in cervical cancer, warranting the use of IDO inhibitors in future clinical trials

Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

Tumors avoid destruction by cytotoxic T cells (CTL) and natural killer (NK) cells by downregulation of classical human leukocyte antigens (HLA) and overexpression of non-classical HLA. This is the first study to investigate HLA expression in relation to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)), clinicopathological parameters and survival in a large cervical cancer patient cohort. Classical (HLA-A and HLA-B/C)- and non-classical HLA molecules (HLA-E and HLA-G) were studied on primary tumors and paired lymph node (LN) metastases from cervical cancer patients (n = 136) by immunohistochemistry. The Chi2 test was used for the comparison of clinicopathological characteristics between SCC and AC patients. The Related-Samples Wilcoxon Signed Rank test was used to compare HLA expression between the primary tumor and metastasis in LN. Patient survival rates were analyzed by Kaplan-Meier curves and Log Rank test. The Mann-Whitney U Test was used to compare the distribution of HLA class I expression between SCC and AC. Decreased expression of HLA-A (SCC P  < 0.001), HLA-B/C (SCC P  < 0.01; AC P  < 0.01) and total classical HLA (SCC P  < 0.001; AC P = 0.02) was apparent in metastatic tumor cells compared to the primary tumor. In primary SCC, there was a clear trend towards complete loss of HLA-A (P = 0.05). SCC metastases showed more complete loss of HLA-A, while AC metastases showed more complete loss of HLA-B/C (P = 0.04). In addition, tumor size and parametrium involvement were also related to aberrant HLA class I expression. No significant associations between HLA expression and disease-specific (DSS) or disease-free survival (DFS) were found in this advanced disease cohort. However, in the SCC group, samples showing loss of HLA-A or loss of total classical HLA but positive for HLA-G were linked to poor patient survival (DSS P = 0.001 and P = 0.01; DFS P = 0.003 and P = 0.01, for HLA-A and total classical HLA, respectively). These results strengthen the idea of tumor immune escape variants leading to metastasis. Moreover, SCC tumors showing downregulation of HLA-A or total classical HLA in combination with HLA-G expression had poor prognosis. Our findings warrant further analysis of HLA expression as a biomarker for patient selection for CTL- and NK- cell based immunotherapeutic interventio

High and Interrelated Rates of PD-L1+CD14+ Antigen-Presenting Cells and Regulatory T Cells Mark the Microenvironment of Metastatic Lymph Nodes from Patients with Cervical Cancer

A better understanding of the microenvironment in relation to lymph node metastasis is essential for the development of effective immunotherapeutic strategies against cervical cancer. In the present study, we investigated the microenvironment of tumor-draining lymph nodes of patients with cervical cancer by comprehensive flow cytometry-based phenotyping and enumeration of immune-cell subsets in tumor-negative (LN(-), n = 20) versus tumor-positive lymph nodes (LN(+), n = 8), and by the study of cytokine release profiles (n = 4 for both LN(-) and LN(+)). We found significantly lower CD4(+) and higher CD8(+) T-cell frequencies in LN(+) samples, accompanied by increased surface levels of activation markers (HLA-DR; ICOS; PD-1; CTLA-4) and the memory marker CD45RO. Furthermore, in LN(+), we found increased rates of a potentially regulatory antigen-presenting cell (APC) subset (CD11c(hi)CD14(+)PD-L1(+)) and of myeloid-derived suppressor cell subsets; the LN(+) APC subset correlated with significantly elevated frequencies of FoxP3(+) regulatory T cells (Treg). After in vitro stimulation with different Toll-like receptor (TLR) ligands (PGN; Poly-IC; R848), we observed higher production levels of IL6, IL10, and TNFα but lower levels of IFNγ in LN(+) samples. We conclude that, despite increased T-cell differentiation and activation, a switch to a profound immune-suppressive microenvironment in LN(+) of patients with cervical cancer will enable immune escape. Our data indicate that the CD14(+)PD-L1(+) APC/Treg axis is a particularly attractive and relevant therapeutic target to specifically tackle microenvironmental immune suppression and thus enhances the efficacy of immunotherapy in patients with metastasized cervical cancer. Cancer Immunol Res; 3(1); 48-58. ©2014 AAC

Additional file 2: Figure S1. of Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

Survival plots of HLA expression in the primary tumor and paired metastatic tumor samples. 5-years disease specific survival (DSS) rates for patients with cervical SCC (A) and AC (B) in relation to HLA-A, HLA-B/C, total classical HLA, HLA-E and HLA-G expression in primary tumor cells and paired metastases. P-value was calculated by Log rank test. (TIF 20952 kb

Additional file 1: Table S1. of Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

HLA Expression pattern comparison between primary tumor and metastatic tumor samples. (DOC 56 kb

Indoleamine 2,3-dioxygenase expression pattern in the tumor microenvironment predicts clinical outcome in early stage cervical cancer

The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however, information about the relationship between serum levels and IDO expression in the tumor is lacking. IDO expression was studied in 71 primary and 14 paired metastatic cervical cancer samples by various immunohistochemical (IHC) techniques, including 7-color fluorescent multiparameter IHC, and the link between the concentration of IDO metabolites in serum, clinicopathological characteristics, and the presence of (proliferating) T cells (CD8, Ki67, and FoxP3) was examined. In addition, we compared the relationships between IDO1 and IFNG gene expression and clinical parameters using RNAseq data from 144 cervical tumor samples published by The Cancer Genome Atlas (TCGA). Here, we demonstrate that patchy tumor IDO expression is associated with an increased systemic kyn/trp ratio in cervical cancer (P = 0.009), whereas marginal tumor expression at the interface with the stroma is linked to improved disease-free (DFS) (P = 0.017) and disease-specific survival (P = 0.043). The latter may be related to T cell infiltration and localized IFNγ release inducing IDO expression. Indeed, TCGA analysis of 144 cervical tumor samples revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels (P < 0.001) and a significant association with improved DFS for high IDO1 and IFNG transcript levels (P = 0.031). Unexpectedly, IDO+ tumors had higher CD8+Ki67+ T cell rates (P = 0.004). Our data thus indicate that the serum kyn/trp ratio and IDO expression in primary tumor samples are not clear-cut biomarkers for prognosis and stratification of patients with early stage cervical cancer for clinical trials implementing IDO inhibitors. Rather, a marginal IDO expression pattern in the tumor dominantly predicts favorable outcome, which might be related to IFNγ release in the cervical tumor microenvironment

image_1_Indoleamine 2,3-Dioxygenase Expression Pattern in the Tumor Microenvironment Predicts Clinical Outcome in Early Stage Cervical Cancer.tif

<p>The indoleamine 2,3-dioxygenase (IDO) enzyme can act as an immunoregulator by inhibiting T cell function via the degradation of the essential amino acid tryptophan (trp) into kynurenine (kyn) and its derivates. The kyn/trp ratio in serum is a prognostic factor for cervical cancer patients; however, information about the relationship between serum levels and IDO expression in the tumor is lacking. IDO expression was studied in 71 primary and 14 paired metastatic cervical cancer samples by various immunohistochemical (IHC) techniques, including 7-color fluorescent multiparameter IHC, and the link between the concentration of IDO metabolites in serum, clinicopathological characteristics, and the presence of (proliferating) T cells (CD8, Ki67, and FoxP3) was examined. In addition, we compared the relationships between IDO1 and IFNG gene expression and clinical parameters using RNAseq data from 144 cervical tumor samples published by The Cancer Genome Atlas (TCGA). Here, we demonstrate that patchy tumor IDO expression is associated with an increased systemic kyn/trp ratio in cervical cancer (P = 0.009), whereas marginal tumor expression at the interface with the stroma is linked to improved disease-free (DFS) (P = 0.017) and disease-specific survival (P = 0.043). The latter may be related to T cell infiltration and localized IFNγ release inducing IDO expression. Indeed, TCGA analysis of 144 cervical tumor samples revealed a strong and positive correlation between IDO1 and IFNG mRNA expression levels (P < 0.001) and a significant association with improved DFS for high IDO1 and IFNG transcript levels (P = 0.031). Unexpectedly, IDO+ tumors had higher CD8⁺Ki67⁺ T cell rates (P = 0.004). Our data thus indicate that the serum kyn/trp ratio and IDO expression in primary tumor samples are not clear-cut biomarkers for prognosis and stratification of patients with early stage cervical cancer for clinical trials implementing IDO inhibitors. Rather, a marginal IDO expression pattern in the tumor dominantly predicts favorable outcome, which might be related to IFNγ release in the cervical tumor microenvironment.</p