Prognostic Value and Risk Factors of Treatment-Related Lymphopenia in Malignant Glioma Patients Treated With Chemoradiotherapy: A Systematic Review and Meta-Analysis

Background: Immunotherapy has shown promising therapeutic efficacy in various cancers but not gliomas. Circulating lymphocytes play critical roles in cancer control and responses to immune checkpoint inhibitors. Treatment-related lymphopenia has been associated with poor survival in patients with various tumors. This meta-analysis evaluated the risk and impact of lymphopenia in patients with glioma.Methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were comprehensively searched. Eligible studies were included if they reported the incidence and risk factors of lymphopenia and the impact of lymphopenia on survival. Stata 16.0 was used for this meta-analysis.Results: A total of 21 studies were included in the final systematic review and 20 were included in the quantitative analysis. The overall incidence of grade III/IV lymphopenia was 31.6% [95% confidence interval (CI), 22.3–40.8%]. Pooled results based on pathology of glioma revealed that the incidence in astrocytoma and astrocytoma oligodendroglioma patients was 20.2% (95% CI:5.9–34.4%), and the incidence in glioblastoma patients was 27.6% (95% CI:16.2–38.9%). Lymphopenia was associated with poor overall survival (hazard ratio, 1.99; 95% CI, 1.74–2.27; P< 0.001) compared to no lymphopenia. Brain receiving radiation dose of 20 or 25 Gy, female sex, older age, lower baseline lymphocyte count, and dexamethasone dose > 2 mg instead of baseline use were risk factors for lymphopenia.Conclusions: Treatment-related lymphopenia was associated with decreased survival in patients with glioma. Optimization of chemoradiation regimens, particularly in patients with concurrent risk factors, can reduce lymphopenia and potentially improve survival in the era of immunotherapy.

Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity

Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFNγ (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.

Alterations of circulating lymphocyte subsets in patients with colorectal carcinoma

Introduction Cellular immune response to cancer is known to be of great importance for tumor control. Moreover, solid tumors influence circulating lymphocytes, which has been shown for several types of cancer. In our prospective study we elucidate changes in lymphocyte subsets in patients with colorectal carcinoma compared to healthy volunteers. Methods Flow cytometry was performed at diagnosis of colon carcinoma to analyze B cells, T cells and NK cells including various subtypes of each group. Univariate and multivariate analyses including age, gender, tumor stage, sidedness and microsatellite instability status (MSI) were performed. Results Forty-seven patients and 50 healthy volunteers were included. Median age was 65 years in patients and 43 years in the control group. Univariate analysis revealed lower total lymphocyte counts, lower CD4 + cells, CD8 + cells, B cells and NKs including various of their subsets in patients. In multivariate analysis patients had inferior values of B cells, CD4 + cells and NK cells and various subsets, regardless of age and gender. Naïve, central memory and HLADR + CD8 + cells showed an increase in patients whereas all other altered subsets declined. MSI status had no influence on circulating lymphocytes except for higher effector memory CD8 + cells in MSI-high patients. Localization in the left hemicolon led to higher values of total cytotoxic T cells and various T cell subsets. Conclusion We found significant changes in circulating lymphocyte subsets in colon carcinoma patients, independent of physiological alterations due to gender or age. For some lymphocyte subsets significant differences according to tumor localization or MSI-status could be seen.

Immunological and Preventive Effects of Hochuekkito and Kakkonto Against Coronavirus Disease in Healthcare Workers: A Retrospective Observational Study

Amid the global outbreak of coronavirus disease 2019 (COVID-19), it may be expected that low-toxicity natural compounds, such as Kampo formulas, will have a preventive effect on COVID-19. Although the biological properties and safety of the representative Kampo compounds, hochuekkito (HET) and kakkonto (KKT), have been confirmed in various animal model experiments, clinical studies, and a few human studies to induce biological effects on various infectious diseases without significant toxicity, it is unclear whether HET and KKT are safe and effective for COVID-19 prevention. The study population included healthcare workers (HCWs), as they are at a higher risk of infection than the other populations. We retrospectively investigated the immunological and preventive effects of HET and KTT against COVID-19. We included 27 HCWs (aged 21–72 years, F:M = 18:9) from hospitals and clinics of the Hokuriku-Tokai region. The HCWs received HET and KKT for general fatigue and myalgia during this period for 28 days. We obtained patient clinical data from electronic medical records. We analyzed the changes in immunomodulation before and after the administration of the formulas from residual specimens based on the expression of relevant surface markers. The specimens were also tested for the presence of antibodies against severe acute respiratory syndrome coronavirus 2. The following side effects were reported: abdominal discomfort in five patients, diarrhea in two, and loose or soft stool in three. All 27 HCWs tested negative for COVID-19 antibodies. HET and KKT administration significantly increased the absolute number of circulating lymphocytes expressing the activating receptors NKp46, NKp30, and suppressing receptor NKG2A. There was also a significant increase in the absolute number of circulating lymphocytes expressing the receptors TLR4, OX40, 4–1BB, GITR, PD-1, and ICOS. These data indicate that HET and KKT can enhance and modulate NK activity in circulating human immune cells. The immunomodulatory effects, such as activation and regulation of T cells, are consistent with a putative improvement in infectious immunosurveillance. An increase in the number of T cells and CD4/CD8-positive cells indicates an enhanced ability to protect against infection. HET and KKT may prevent the onset or worsening of COVID-19 through their immunomodulatory effects.

A Rational Approach to Unilateral Neck RT for Head and Neck Cancers in the Era of Immunotherapy

Radiotherapy plays an important role in the definitive and adjuvant treatment of head and neck squamous cell carcinoma (HNSCC). However, standard courses of radiation therapy may contribute to the depletion of circulating lymphocytes and potentially attenuate optimal tumor antigen presentation that may be detrimental to the efficacy of novel immunotherapeutic agents. This review explores the advantages of restricting radiation to the primary tumor/tumor bed and ipsilateral elective neck as it pertains to the evolving field of immunotherapy.

Oral glucose feeding enhances adherence of quiescent lymphocytes to fibronectin via non-canonical insulin signalling.

Impaired glucose metabolism is associated with chronic inflammation, aberrant immunity and anomalous leukocyte trafficking. Conversely, infusion of functional immune cells restores glucose metabolism. Despite being exposed to periodic alterations in blood insulin levels upon fasting and feeding, studies exploring the physiological effects of these hormonal changes on quiescent circulating lymphocytes are missing. Here we find that oral glucose load in healthy men and mice enhance adherence of circulating peripheral blood mononuclear cells (PBMCs) to fibronectin. This led to increased homing of post-load PBMCs to injured blood vessels. Cell culture based experiments on Jurkat-T cells and PBMCs demonstrated that insulin elicits these adhesive effects through a non-canonical signalling involving insulin growth factor-1 receptor (IGF-1R) and phospholipase C gamma-1 (PLCγ-1) mediated activation of integrin β1. Our findings point to the relevance of post-prandial insulin spikes in regulating homing of circulating T-cells to various organs for tissue repair and immunity.

Estimation of lymphocyte radiation doses after the ingestion of radionuclides of different tropicity

Assessment of the lymphocyte doses is relevant for solving a number of radiobiological problems, including the risk assessment of hemoblastosis (leukemia, multiple myeloma, lymphoma etc.), as well as the use of circulating lymphocytes as “natural biodosimeters”. The latter is because the frequency of chromosomal aberrations occurring in lymphocytes following radiation exposure is proportional to the accumulated dose. Assessment of doses to the circulating lymphocytes requires due account of: first, the dose accumulated by the lymphocyte progenitors in the red bone marrow; and second, the dose accumulated during lymphocyte circulation through lymphoid organs. The models presented by International Commission on Radiological Protection (ICRP-67, ICRP-100) allow calculating the dose for specific lymphoid organs based on known level of radionuclide intakes. A recently developed model of circulating T-lymphocyte irradiation takes into account all sources of exposure and age-related dynamics of T-lymphocytes: (1) exposure of lymphocyte progenitors in red bone marrow: (2) exposure of T-lymphocytes in the lymphoid organs, taking into account the proportion of resident lymphocytes and the residence time of circulating lymphocytes in the specific lymphoid organs. The objective of the study is to assess the dose coefficients allowing for the transition from the ingestion of 141,144Ce, 95Zr, 103,106Ru, 95Nb to the doses accumulated in circulating T-lymphocytes. For calculations, we used the dose coefficients from ICRP publications for specific lymphoid organs, as well as published data on the residence time of circulating lymphocytes in lymphoid organs and tissues. As a result, it was shown that the doses in circulating T-lymphocytes are higher than those in the red bone marrow, but lower than the doses to the colon wall. The dose coefficients were age dependent; the maximum values were typical for newborns. The obtained dose coefficients for 141,144Ce, 95Zr, 95Nb and 103,106Ru can be used to estimate the tissue and organ doses based on data on the frequency of chromosomal aberrations in peripheral blood lymphocytes.