The role and importance of neutrophils in cancer has become increasingly apparent over the past decade. Neutrophils accumulate in the peripheral blood of patients with cancer, especially in those with advanced-stage disease, and a high circulating neutrophil-to-lymphocyte ratio is a robust biomarker of poor clinical outcome in various cancers. To date, most studies investigating the role of neutrophils in cancer have involved animal models or investigated the function of circulating human neutrophils. Thus, only limited information is available on the roles of intratumoural neutrophils (also known as tumour-associated neutrophils (TANs)) in patients with cancer. In this Review, we initially describe the evidence correlating the neutrophil-to-lymphocyte ratio with prognosis, followed by a discussion on the predictive value of TANs, which remains debatable, with conflicting data from different cancer types, including variations based on neutrophil location within and/or around the tumour. We then explore available data on the implications of TAN phenotypes and functions for cancer development and progression, highlighting the reported effects of various treatments on TANs and how neutrophils might affect therapeutic efficacy. Finally, we examine the various compounds capable of modulating neutrophils and suggest future research directions that might ultimately enable the manipulation of TANs in patients with cancer.

Tumour-associated neutrophils in patients with cancer

There is abundant evidence that tumor-infiltrating CD8+ T cells contribute positively to antitumor immunity; however, the role of tumor-infiltrating B cells (TIL-B) and plasma cells (PC) remains controversial, leading to differing opinions about whether immunotherapies should be designed to enhance or inhibit these cells. Through a comprehensive PubMed search, we reviewed publications with cohorts of 50 or more cases in which the prognostic value of TIL-B/PC was assessed by immunohistochemistry and/or gene-expression analysis. Sixty-nine studies representing 19 cancers met our review criteria. The large majority of studies assessed TIL-B by immunohistochemical detection of CD20. Of these, 50.0% reported a positive prognostic effect for CD20+ TIL-B, whereas the remainder found a neutral (40.7%) or negative (9.3%) effect. These differences in prognostic effect were not attributable to cancer type, other clinicopathologic factors, or differing technical approaches. The prognostic significance of TIL-B/PC was generally concordant with that of CD3+ and/or CD8+ T cells, and the prognostic effect of T cells was generally stronger when TIL-B and/or PC were also present. Additionally, 21 studies inferred the presence of TIL-B/PC from gene-expression data, and a large majority reported a positive prognostic effect. Although more studies are required involving additional cancer types and independent patient cohorts, the weight of evidence supports a positive role for TIL-B and PC in antitumor immunity, suggesting that enhancement of these responses should be considered in the design of cancer immunotherapies.

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Prognostic significance of tumor-infiltrating B cells and plasma cells in human cancer

Immune infiltration of tumors is closely associated with clinical outcome in renal cell carcinoma (RCC). Tumor‐infiltrating immune cells (TIICs) regulate cancer progression and are appealing therapeutic targets. The purpose of this study was to determine the composition of TIICs in RCC and further reveal the independent prognostic values of TIICs. CIBERSORT, an established algorithm, was applied to estimate the proportions of 22 immune cell types based on gene expression profiles of 891 tumors. Cox regression was used to evaluate the association of TIICs and immune checkpoint modulators with overall survival (OS). We found that CD8+ T cells were associated with prolonged OS (hazard ratio [HR] = 0.09, 95% confidence interval [CI].01‐.53; P = 0.03) in chromophobe carcinoma (KICH). A higher proportion of regulatory T cells was associated with a worse outcome (HR = 1.59, 95% CI 1.23‐.06; P < 0.01) in renal clear cell carcinoma (KIRC). In renal papillary cell carcinoma (KIRP), M1 macrophages were associated with a favorable outcome (HR = .43, 95% CI .25‐.72; P < 0.01), while M2 macrophages indicated a worse outcome (HR = 2.55, 95% CI 1.45‐4.47; P < 0.01). Moreover, the immunomodulator molecules CTLA4 and LAG3 were associated with a poor prognosis in KIRC, and IDO1 and PD‐L2 were associated with a poor prognosis in KIRP. This study indicates TIICs are important determinants of prognosis in RCC meanwhile reveals potential targets and biomarkers for immunotherapy development.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.13996

Immune infiltration in renal cell carcinoma.

Immune infiltration of colorectal cancer (CRC) is closely associated with clinical outcome. However, previous work has not accounted for the diversity of functionally distinct cell types that make up the immune response. In this study, based on a deconvolution algorithm (known as CIBERSORT) and clinical annotated expression profiles, we comprehensively analyzed the tumor-infiltrating immune cells present in CRC for the first time. The fraction of 22 immune cells subpopulations was evaluated to determine the associations between each cell type and survival and response to chemotherapy. As a result, profiles of immune infiltration vary significantly between paired cancer and paracancerous tissue and the variation could characterize the individual differences. Of the cell subpopulations investigated, tumors lacking M1 macrophages or with an increased number of M2 macrophages, eosinophils, and neutrophils were associated with the poor prognosis. Unsupervised clustering analysis using immune cell proportions revealed five subgroups of tumors, largely defined by the balance between macrophages M1, M2, and NK resting cells, with distinct survival patterns, and associated with well-established molecular subtype. Collectively, our data suggest that subtle differences in the cellular composition of the immune infiltrate in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and response to treatment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.1745

Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

Objectives In non-small cell lung cancer (NSCLC), the immune system and possibly its composition affect survival. In this in silico study, the immune infiltrate composition in NSCLC patients was evaluated. Methods Gene expression data of tumors from early NSCLC patients were obtained from Gene Expression Omnibus (GEO). With CIBERSORT, 22 immune cell fractions were estimated. Results The immune infiltrate of 1430 pretreatment NSCLC patients contained mostly plasma cells, macrophages and CD8 T cells. Higher fractions of resting mast and CD4 T-helper cells were associated with longer overall survival (OS) (HR = 0.95, P < 0.01; HR = 0.98, = 0.04, respectively) and higher fractions of M2 macrophages and active dendritic cells with shorter survival (HR = 1.02, P = 0.03; HR = 1.03, P = 0.05, respectively). Adenocarcinoma patients with survival data (n = 587) showed higher fractions of resting mast and resting CD4 T cells, and lower M0 macrophages than squamous cell carcinoma (n = 254), which were associated with OS (HR = 0.95, P = 0.04; HR = 0.97, P = 0.01; HR = 1.03, P = 0.01, respectively). Fractions of memory B cells, naive CD4 T cells and neutrophils had different associations with survival depending on the subtype. Smokers had had higher fractions of regulatory T cell, follicular helper T cell, neutrophil and M2 macrophage, which were associated with shorter survival (HR = 1.3, P < 0.01; HR = 1.13, P = 0.02; HR = 1.09, P = 0.03; HR = 1.04, P = 0.02, respectively). Conclusion Pretreatment differences in immune cell composition in NSCLC are associated with survival and depend on smoking status and histological subtype. Smokers' immune composition is associated with lower survival.

/pdf/immune-microenvironment-composition-in-non-small-cell-lung-h7fz9xtqn7.pdf

Immune microenvironment composition in non-small cell lung cancer and its association with survival.

The prognostic landscape of tumor-infiltrating immune cell and immunomodulators in lung cancer.

Background Lianhua Qingke (LH) tablets is an effective traditional Chinese medicine against various viral infections, especially in relieving coughing. However, its effects on COVID-19 are unknown. Methods To examine the therapeutic effectiveness of LH tablets in COVID-19 patients with mild and common types, a randomized, multicenter, controlled study was carried out. COVID-19 cases were randomized to undergo routine treatment with or without LH tablets (4 tablets, three times a day) for 14 days. The primary endpoints were the rate of achieving clinical symptom resolution and the corresponding time. Results There were 144 participants in the full analysis set (72 each in the LH and control groups). The LH group participants had elevated symptom alleviation rate at 14 days compared with control cases (FAS: 98.61% vs. 84.72%, p = 0.0026). In comparison with control group participants, the LH group participants had reduced median time to clinical symptom alleviation (median: 4 vs. 7 days, p < 0.0001). Higher resolution rates of coughing (98.44% vs. 84.51%, p = 0.0045) and expectoration (100% vs. 82.35%, p = 0.0268) were observed in the LH group. Times to recovery of fever (median: 2 vs. 3 days, p = 0.0007), coughing (median: 4 vs. 7 days, p < 0.0001), and expectoration (median: 3 vs. 6 days, p < 0.0001) were also notably shorter in the LH group. Moreover, the LH group had elevated improvement rates in chest computed tomography signs (FAS: 86.11% vs. 72.22%, p = 0.0402) and clinical cure at day 28 (FAS: 83.33% vs. 68.06%, p = 0.0326). However, no differences were found in the laboratory test and viral assay. Serious adverse events were not detected. Conclusion These preliminary findings indicate LH tablets may be effective in symptomatic COVID-19, especially in relieving coughing. This trial was registered in Chinese Clinical Trial Registry (ChiCTR2100042069).

/pdf/efficacy-and-safety-of-lianhua-qingke-tablets-in-the-2v2q9eq8.pdf

Efficacy and Safety of Lianhua Qingke Tablets in the Treatment of Mild and Common-Type COVID-19: A Randomized, Controlled, Multicenter Clinical Study

Background: Asymptomatic patients are unneglected sources in propagating transmission chain due to their high viral loads. However, treatments available based on symptoms seem not applicable to asymptomatic patients. In this study, the authors want to estimate the effectiveness of Lianhua Qingwen (LH) capsule on asymptomatic coronavirus disease 2019 (COVID-19) patients. Methods: A randomized controlled trial (RCT) was performed to explore the effectiveness and safety of LH capsule in treating asymptomatic COVID-19 patients. Patients were randomized to control group (isolated observation) and treatment group (LH, 4 capsules, thrice daily) for 14 days. The primary endpoints were the rate and time of nucleic acid turning negative during the isolation observation. Results: A total of 120 participants were included in the full analysis set (60 each in the control and treatment groups). Data showed that the rate of nucleic acid turning negative during the isolation observation in the treatment group was higher than that in the control group (rate difference: 21.66%, 95% confidence interval [CI]: 4.34 to 37.27, p = 0.0142). Patients in the treatment group have a shorter time of nucleic acid turning negative (7.5 vs. 14.5 days, p = 0.018). Moreover, the rate of clinical symptoms appearance in the treatment group was lower compared with that in the control group (rate difference: -31.67, 95% CI: -46.83 to -13.82, p = 0.0005). The proportion of confirmed mild and common cases in the treatment group was also lower (35.00% vs. 66.67%, p = 0.0005). No serious adverse events were documented. Conclusions: In this study, the authors illustrated that LH capsule is beneficial to asymptomatic COVID-19 patients. Considering the lack of interventions for treating asymptomatic COVID-19 patients at this stage, LH capsule could be considered as a choice. Chinese Clinical Trial Registry: ChiCTR2100042066.

Effectiveness of Lianhua Qingwen Capsule in Treatment of Asymptomatic COVID-19 Patients: A Randomized, Controlled Multicenter Trial.

Cytokine-induced killer (CIK) cells were isolated and proliferation from human peripheral blood and cultured in appropriate growth medium. The biological characteristics of CIK cells were further determined by the characterization of surface markers by flow cytometry. CIK cells inhibited the proliferation of human lung adenocarcinoma NCL-H157 cells. Vascular endothelial growth factor (VEGF) expression was down-regulated in CIK cells co-cultured with NCL-H157 cells by western blotting analysis. Furthermore, in comparison with cells untreated by CIK, the NCL-H157 had a lower proliferation capacity. We proposed that the pharmacological mechanisms of NCL-H157 promoted by CIK can be estimated possibly with different biological significance that can be ascribed to down-regulated VEGF expression in vitro. The results suggest that the VEGF pathway guides developmental inhibiting of NCL-H157, and we speculate that the function of VEGF pathways is to guide NCL-H157 to inhibition by abundant CIK.

https://www.degruyter.com/downloadpdf/j/med.2016.11.issue-1/med-2016-0001/med-2016-0001.xml

The possible molecular regulation mechanism of CIK cells inhibiting the proliferation of Human Lung Adenocarcinoma NCL-H157 Cells.

BACKGROUND
Lung cancer is the leading cause of cancer death in most countries. Although early diagnosis and treatment critically influences prognosis, lung cancers are generally only discovered in the late stages of the disease.


OBJECTIVE
Widely-used screening and diagnostic methods are not suitable for preventive screening, and high-throughput technologies based on serum biomarkers are needed.


METHOD
We screened 501 serum samples, including 224 lung cancer (LC), 126 disease control (DC) and 151 healthy donor (HC) samples for new serum autoantibodies as biomarkers in the early diagnosis of lung cancer. In phase I, we used HuProtTM microarrays to perform preliminary serum antibody screening on 24 LC and 24 HC samples. In phase II, we screened 60 LC, 60 DC and 60 HC serum samples using focused arrays constructed with 22 of the candidate autoantibody biomarkers screened out in phase I.


RESULTS
After data modeling and validation, we selected four potential early LC protein biomarker candidates, IL2RB, CENPB, TP53, and XAGE1A, with individual specificities >90% and sensitivities ranging from 21.2% to 32.2%. These four biomarkers had a specificity of >90% and a sensitivity of >65.5% for early LC when they combined in a panel. Further evaluation of these four biomarker candidates using ELISA assays and 273 serum samples (140 LC, 66 DC and 67 HC) gave similar results (specificity of >91.7%, sensitivity >61.43%).


CONCLUSION
IL2RB, CENPB, TP53, and XAGE1A combined biomarker panel holds potential for rapid screening and could improve the diagnosis of early-stage LC, thus potentially also improving its prognosis.

Shucai Wu

Papers

The prognostic landscape of tumor-infiltrating immune cell and immunomodulators in lung cancer.

Efficacy and Safety of Lianhua Qingke Tablets in the Treatment of Mild and Common-Type COVID-19: A Randomized, Controlled, Multicenter Clinical Study

Effectiveness of Lianhua Qingwen Capsule in Treatment of Asymptomatic COVID-19 Patients: A Randomized, Controlled Multicenter Trial.

The possible molecular regulation mechanism of CIK cells inhibiting the proliferation of Human Lung Adenocarcinoma NCL-H157 Cells.

Serum Biomarker Panel for Rapid Early Diagnosis of Lung Cancer.