The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient's tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

Understanding the tumor immune microenvironment (TIME) for effective therapy.

Pathogenic human coronaviruses (CoVs), such as the severe acute respiratory syndrome (SARS)-CoV and the Middle East respiratory syndrome-CoV, cause acute respiratory illness. Epidemiological data from the 2002-2003 SARS epidemic and recent Middle East respiratory syndrome outbreak indicate that there may be sex-dependent differences in disease outcomes. To investigate these differences, we infected male and female mice of different age groups with SARS-CoV and analyzed their susceptibility to the infection. Our results showed that male mice were more susceptible to SARS-CoV infection compared with age-matched females. The degree of sex bias to SARS-CoV infection increased with advancing age, such that middle-aged mice showed much more pronounced differences compared with young mice. Enhanced susceptibility of male mice to SARS-CoV was associated with elevated virus titers, enhanced vascular leakage, and alveolar edema. These changes were accompanied by increased accumulation of inflammatory monocyte macrophages and neutrophils in the lungs of male mice, and depletion of inflammatory monocyte macrophages partially protected these mice from lethal SARS. Moreover, the sex-specific differences were independent of T and B cell responses. Furthermore, ovariectomy or treating female mice with an estrogen receptor antagonist increased mortality, indicating a protective effect for estrogen receptor signaling in mice infected with SARS-CoV. Together, these data suggest that sex differences in the susceptibility to SARS-CoV in mice parallel those observed in patients and also identify estrogen receptor signaling as critical for protection in females.

Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection.

Estrogen receptors regulate innate immune cells and signaling pathways.

Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.

https://www.pnas.org/content/pnas/111/2/869.full.pdf

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination

Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis

Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load.

/pdf/elevated-17b-estradiol-protects-females-from-influenza-a-481s0br2hm.pdf

Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses.

Simple Summary The risk of lung cancer occurrence among patients with chronic kidney disease (CKD) is significantly higher than patients with normal renal function. Moreover, the long-term outcomes of CKD patients with lung cancer are poor. We conducted the present nationwide population based study to assess the association between the risk of lung cancer and influenza vaccination. The results showed that among CKD patients, potentially risk reduction of lung cancer was observed after influenza vaccination. In addition, the potentially protective effect of influenza vaccination on lung cancer risk reduction appeared to be dose dependent. The findings of present study provided the additional effect of influenza vaccination among patients with CKD. Abstract Chronic kidney disease (CKD) is significantly associated with lung cancer incidence. The aim of this study was to elucidate whether influenza vaccination reduces the incidence of lung cancer in patients with CKD. This cohort study enrolled patients with a record of CKD diagnosis from 2000 to 2012 in Taiwan’s National Health Insurance Research Database. Included patients were divided into vaccinated and unvaccinated groups. In total 12,985 patients with CKD were enrolled. Among these patients, 5495 were vaccinated and 7490 were unvaccinated. The risk of lung cancer was significantly lower in the influenza vaccination group after adjusting for age, sex, dialysis status, lung diseases, comorbidities, level of urbanization, and monthly income (adjusted hazard ratio (HR): 0.50, 95% confidence interval (CI; 0.38–0.65), p < 0.05). Lower risk of lung cancer was observed in both sexes, all age groups, dialysis status and co-existed lung diseases. The association between the risk of lung cancer and vaccination appeared to be dose-dependent (adjusted HRs: 0.91 (0.66–1.25), 0.49 (0.34–0.71), and 0.25 (0.17–0.38) for patients who received 1, 2 or 3, and ≥4 vaccinations during the follow-up period, respectively). In conclusion, Influenza vaccination decreased the risk of lung cancer in patients diagnosed with CKD. This potentially protective effect against lung cancer appeared to be dose dependent.

/pdf/influenza-vaccination-and-risk-of-lung-cancer-in-patients-3djsrupa.pdf

Influenza Vaccination and Risk of Lung Cancer in Patients with Chronic Kidney Disease: A Nationwide, Population-Based Cohort Study

Patients with type 2 diabetes mellitus (T2DM) have a higher risk of chronic kidney disease (CKD) due to vascular complications and chronic inflammation. T2DM contributes to a higher risk of mortality and morbidity related to influenza. In Taiwan, influenza vaccination is recommended for patients with T2DM. A previous meta-analysis reported the efficacy of influenza vaccination in reducing hospitalization and mortality in patients with diabetes; however, the renal protective effect of the vaccine remains unclear. This study evaluated whether influenza vaccination could reduce the incidence of CKD and dialysis in patients with T2DM. The study cohort included all patients aged ≥55 years who were diagnosed as having T2DM between 1 January 2000 and 31 December 2012, by using data from Taiwan’s National Health Insurance Research Database. Each patient was followed up with to assess factors associated with CKD. A time-dependent Cox proportional hazard regression model after adjustment for potential confounders was used to calculate the hazard ratio (HR) of CKD in the vaccinated and unvaccinated patients. The study population comprised 48,017 eligible patients with DM; 23,839 (49.7%) received influenza vaccination and the remaining 24,178 (50.3%) did not. The adjusted HRs (aHRs) for CKD/dialysis decreased in the vaccinated patients compared with the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs: 0.47/0.47, 0.48/0.49, and 0.48/0.48, respectively, all p < 0.0001). We observed similar protective effects against CKD during the influenza and noninfluenza seasons. Regardless of comorbidities or drug use, influenza vaccination was an independent protective factor. Furthermore, aHRs for CKD/dialysis were 0.71 (0.65–0.77)/0.77 (0.68–0.87), 0.57 (0.52–0.61)/0.69 (0.56–0.70), and 0.30 (0.28–0.33)/0.28 (0.24–0.31) in the patients who received 1, 2–3, and ≥4 vaccinations during the follow-up period, respectively. This population-based cohort study demonstrated that influenza vaccination exerts a dose-dependent and synergistic protective effect against CKD in the patients with T2DM with associated risk factors.

/pdf/effect-of-influenza-vaccination-on-the-reduction-of-the-1ucuq0i4.pdf

Effect of Influenza Vaccination on the Reduction of the Incidence of Chronic Kidney Disease and Dialysis in Patients with Type 2 Diabetes Mellitus

Various adverse events and complications have been attributed to COVID-19 (coronavirus disease 2019) vaccinations, which can affect the cardiovascular system, with conditions such as myocarditis, thrombosis, and ischemia. The aim of this study was to combine noninvasive pulse measurements and frequency domain analysis to determine if the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) vaccination and its accompanying cardiovascular side effects will induce changes in arterial pulse transmission and waveform. Radial blood pressure waveform and photoplethysmography signals were measured noninvasively for 1 min in 112 subjects who visited Shuang-Ho Hospital for a BNT162b2 vaccination. Based on side effects, each subject was assigned to Group N (no side effects), Group CV (cardiac or vascular side effects), Group C (cardiac side effects only), or Group V (vascular side effects only). Two classification methods were used: (1) machine-learning (ML) analysis using 40 harmonic pulse indices (amplitude proportions, phase angles, and their variability indices) as features, and (2) a pulse-variability score analysis developed in the present study. Significant effects on the pulse harmonic indices were noted in Group V following vaccination. ML and pulse-variability score analyses provided acceptable AUCs (0.67 and 0.80, respectively) and hence can aid discriminations among subjects with cardiovascular side effects. When excluding ambiguous data points, the AUC of the score analysis further improved to 0.94 (with an adopted proportion of around 64.1%) for vascular side effects. The present findings may help to facilitate a time-saving and easy-to-use method for detecting changes in the vascular properties associated with the cardiovascular side effects following BNT162b2 vaccination.

/pdf/machine-learning-analyses-revealed-distinct-arterial-pulse-1rceywu1.pdf

Machine Learning Analyses Revealed Distinct Arterial Pulse Variability According to Side Effects of Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)

The risk of stroke in patients with gout is high. The effect of vaccines in lowering the stroke risk in patients with gout remains unclear. We retrospectively analyzed 23,949 patients with gout (age ≥ 55 years) from the National Health Insurance Research Database over a 12-year period. The patients were divided into vaccinated (n = 11,649) and unvaccinated groups (n = 12,300). Overall, the vaccinated group had significantly lower risks of all stroke, hemorrhagic stroke, and ischemic stroke than the unvaccinated group (adjusted hazard ratio [aHR], 0.59 and 95% confidence interval [CI], 0.55–0.63; aHR, 0.60 and 95% CI, 0.49–0.73; and aHR, 0.60 and 95% CI, 0.55–0.65, respectively). The association appeared to be dose-dependent for both hemorrhagic and ischemic stroke (hemorrhagic stroke: aHR, 0.81 and 95% CI, 0.61–1.08; aHR, 0.80 and 95% CI, 0.62–1.02; and aHR, 0.37 and 95% CI, 0.28–0.48; ischemic stroke: aHR, 0.83 and 95% CI, 0.74–0.94; aHR, 0.73 and 95% CI, 0.65–0.81; and aHR, 0.42 and 95% CI, 0.38–0.47 for patients vaccinated 1, 2 or 3, and ≥4 times, respectively, during the follow-up period). Patients with a history of atrial fibrillation did not have a lower risk of hemorrhagic stroke even after receiving four vaccinations (aHR, 0.59; 95% CI, 0.25–1.38). Influenza vaccination was associated with a lower risk of all stroke in people with gout, and the association appeared to be dose-dependent.

/pdf/association-between-stroke-risk-and-influenza-vaccination-in-dnopu82p.pdf

William Jian

Papers

Elevated 17β-estradiol protects females from influenza A virus pathogenesis by suppressing inflammatory responses.

Influenza Vaccination and Risk of Lung Cancer in Patients with Chronic Kidney Disease: A Nationwide, Population-Based Cohort Study

Effect of Influenza Vaccination on the Reduction of the Incidence of Chronic Kidney Disease and Dialysis in Patients with Type 2 Diabetes Mellitus

Machine Learning Analyses Revealed Distinct Arterial Pulse Variability According to Side Effects of Pfizer-BioNTech COVID-19 Vaccine (BNT162b2)

Association between Stroke Risk and Influenza Vaccination in Patients with Gout: A Nationwide Population-Based Study