The peripheral CD4+ T cells predict efficacy in non-small cell lung cancer (NSCLC) patients with the anti-PD-1 treatment.

Background: Programmed cell death protein 1 (PD-1) inhibitor therapy has become a routine treatment for advanced non-small cell lung cancer (NSCLC). However, only some NSCLC patients would benefit from anti-PD-1 therapy. We urgently need to identify biomarkers associated with clinical response to change treatment strategies promptly for patients who fail to benefit from anti-PD-1 treatment. This study was aimed to explore whether circulating CD4+ T cells and CD8+ T cells could be biomarkers for predicting anti-PD-1 efficacy. Methods: In this study, 118 NSCLC patients who received anti-PD-1 therapy were enrolled. The percentages of circulating CD4+ T cells and CD8+ T cells before and after anti-PD-1 treatment were determined by flow cytometry. The programmed cell death ligand 1 (PD-L1) expression of tumor tissues was detected by immunocytochemistry. The anti-PD-1 treatment efficacy was assessed by immune response evaluation criteria in solid tumors (iRECIST). Results: The percentage of CD4+ T cells and CD4+/CD8+ ratio in the peripheral blood (PB) was significantly elevated after anti-PD-1 treatment. In contrast, the percentage of CD8+ T cells in the PB was significantly decreased after anti-PD-1 treatment. Furthermore, we found that the percentages of CD4+ T cells and CD4+/CD8+ ratios considerably increased, and the percentages of CD8+ T cells significantly reduced in the effective group. On the contrary, the patients in the ineffective group showed no significant differences in the biomarkers. Multivariate logistic revealed that the percentage of CD4+ T cells at baseline was an independent predictor of anti-PD-1 treatment. The area under the curve (AUC) of the CD4+ T cells percentage was 0.7834 with a cut-off value of 28.53% (sensitivity =82.5%, specificity =66.23%). Conclusions: The percentage of CD4+ T cells at baseline could predict anti-PD-1 efficacy in NSCLC patients.

Inflammatory Biomarker Reduction With Fostemsavir Over 96 Weeks in Heavily Treatment-Experienced Adults With Multidrug-Resistant HIV-1 in the BRIGHTE Study.

Background: Fostemsavir, a first-in-class attachment inhibitor that binds to the viral envelope protein gp120, is approved for heavily treatment-experienced persons with HIV-1 with limited treatment options. We explored changes in immunologic and coagulopathy parameters in the BRIGHTE study: a phase 3 trial that evaluated fostemsavir plus optimized background therapy in heavily treatment-experienced adults with multidrug-resistant HIV-1. Methods: CD4+ T-cell count, CD4+/CD8+ ratio, soluble CD14, soluble CD163, and D-dimer levels were measured through 96 weeks in participants with 1 or 2 fully active antiretroviral agents available at screening. No formal statistical analyses were performed. Results: Among 272 participants, increases were observed from baseline to week 96 in CD4+ T-cell count (mean increase, +205 cells/mm3) and CD4+/CD8+ ratio (mean increase, +0.24). The proportion of observed participants with a CD4+/CD8+ ratio ≥0.45 increased from 9% (25/272) at baseline to 40% (85/213) at week 96. From baseline to week 96, we also observed trends toward decreases in the following (mean [SD] change): soluble CD14, -738.2 (981.8) µg/L; soluble CD163, -138.0 (193.4) µg/L; and D-dimer, -0.099 (0.521) mg/L fibrinogen-equivalent units. Decreases in biomarkers were generally observed among subgroups by baseline disease characteristics, virologic response, and CD4+ T-cell count. Conclusions: These data suggest that heavily treatment-experienced persons with multidrug-resistant HIV-1 treated with fostemsavir + optimized background therapy may have improvements in immune parameters, including markers of monocyte activation and coagulopathy. Clinical Trials Registration: NCT02362503 (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT02362503).

Trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio in patients with HIV and long-term virological suppression based on Yunnan HIV cohort.

OBJECTIVE: Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. METHODS: This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. RESULTS: A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/µL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/µL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. CONCLUSIONS: Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

Risk of developing high-grade squamous intraepithelial lesions or anal cancer after anal condylomata treatment in people living with HIV.

AIM: To assess the risk and natural history of developing advanced anal disease after diagnosis of anal condyloma in people living with HIV (PLWH). METHODS: This was a single-centre retrospective cohort study of PLWH and anal condyloma from 2001 to 2021. Patients who developed advanced anal disease (AAD; anal high-grade squamous intraepithelial lesions and/or anal cancer) were compared to those who did not progress (non-AAD). We assessed the potential association between AAD and condyloma location, recurrence, and treatment modality. AAD-free survival was calculated utilizing Kaplan-Meier methods. RESULTS: A total of 118 PLWH and anal condyloma were included. Mean overall follow-up time was 9.3 years. A total of 31% of patients developed AAD (n = 37). Average time to AAD from condyloma diagnosis was 5.6 years. On multivariate analysis, risk for AAD development was associated with perianal location of condyloma (OR 4.39, p = 0.038) and increased time from initial condyloma diagnosis (OR 1.12, p = 0.008). Higher CD4/CD8 ratios were associated with lower risk of AAD (OR 0.15, p = 0.029). Condyloma recurrence and treatment type were not associated with development of AAD. AAD-free survival was longer in those with intra-anal only condyloma versus those with either perianal disease alone or combined intra-anal/perianal disease (mean survival times: 22.8 vs. 8.7 vs. 10.7 years, p = 0.017). CONCLUSION: Our study demonstrates the need for careful, long-term follow-up of PLWH and condyloma, particularly in the setting of perianal disease and low CD4/CD8 ratio. Risk of anal disease progression is present even in the setting of condyloma regression following treatment.

Impact of neoadjuvant chemotherapy on perioperative immune function in breast cancer patients: a propensity score-matched retrospective study.

To evaluate the impact of neoadjuvant chemotherapy on perioperative immune function in breast cancer patients, focusing on CD3+, CD4+, CD8+, and natural killer (NK) cells, as well as the CD4+/CD8+ ratio. We retrospectively reviewed medical records of breast cancer patients who underwent surgery with or without neoadjuvant chemotherapy at our medical center from January 2020 to December 2022. Patients were matched 1:1 based on propensity scores. Immune cell proportions and the CD4+/CD8+ ratio were compared on preoperative day one and postoperative days one and seven. Among matched patients, immune cell proportions and the CD4+/CD8+ ratio did not significantly differ between those who received neoadjuvant chemotherapy and those who did not at any of the three time points. Similar results were observed in chemotherapy-sensitive patients compared to the entire group of patients who did not receive neoadjuvant chemotherapy. However, chemotherapy-insensitive patients had significantly lower proportions of CD4+ and NK cells, as well as a lower CD4+/CD8+ ratio, at all three time points compared to patients who did not receive neoadjuvant chemotherapy. Neoadjuvant chemotherapy may impair immune function in chemotherapy-insensitive patients, but not in those who are sensitive to the treatment.

The persistence of low CD4/CD8 ratio in chronic HIV-infection, despite ART suppression and normal CD4 levels, is associated with pre-therapy values of inflammation and thymic function.

BACKGROUND: Persistence of a low CD4/CD8 ratio is associated with an increased morbimortality in people living with HIV (PLWH) under effective antiretroviral therapy. We aimed to explore the immunological significance of a persistently low CD4/CD8 ratio, even despite normal CD4 levels, and assess whether these features vary from those associated to a low nadir-CD4, another well-established predictor of disease progression. METHODS: CD4-recovered PLWH were classified by CD4/CD8 ratio after three-years of ART (viral suppression, CD4≥500; R < 0.8, n = 24 and R > 1.2, n = 28). sj/ß-TRECs ratio and inflammatory-related markers were quantified. PBMCs were immunophenotyped by CyTOF and functionally characterized by ELISPOT. Subjects were also reclassified depending on nadir-CD4 (N ≤ 350/N > 350). RESULTS: R < 0.8 showed a differential inflammatory profile compared to R > 1.2 (increased ß2-microglobulin, D-dimers and IP-10 before ART). R < 0.8 presented lower baseline thymic function, being inversely correlated with post-ART inflammation. R < 0.8 at follow-up showed most alterations in CD8 subsets (increasing frequency and exhibiting a senescent phenotype [e.g., CD57+, CD95+]) and enhanced T-cell IFNγ/IL-2 secretion. However, comparing N ≤ 350 to N > 350, the main features were altered functional markers in CD4 T-cells, despite no differences in maturational subsets, together with a restricted T-cell cytokine secretion pattern. CONCLUSION: Persistence of low CD4/CD8 ratio in successfully-treated PLWH, with normal CD4 counts, is associated with baseline inflammation and low thymic function, and it features post-therapy alterations specific to CD8 T-cells. Differently, subjects recovered from low nadir-CD4 in this setting feature post-therapy alterations on CD4 T-cells. Hence, different mechanisms of disease progression could underlie these biomarkers, potentially requiring different clinical approaches.

Immunological and Haematological Relevance of Helminths and Mycobacterium tuberculosis Complex Coinfection among Newly Diagnosed Pulmonary Tuberculosis Patients from Bobo-Dioulasso, Burkina Faso.

The effect of helminthiasis on host immunity is a neglected area of research, particularly in tuberculosis (TB) infection. This study aimed to evaluate the effect of helminthiasis on immunological and haematological parameters in newly diagnosed TB patients in Bobo-Dioulasso. After all biological analyses, we formed three subpopulations: group 1 (n = 82), as control, were participants without helminthic or Mycobacterium tuberculosis complex infection (Mtb-/Helm-), group 2 (n = 73) were TB patients without helminthic infection (Mtb+/Helm-), and group 3 (n = 22) were TB patients with helminthic infection (Mtb+/Helm+). The proportion of helminth coinfection was 23.16% (22/95) in TB patients, and Schistosoma mansoni infection was found in 77.3% (17/22) cases of helminthiasis observed in this study. A low CD4 T cell count and a low CD4:CD8 ratio were significantly associated with concomitant infection with helminths and the Mtb complex (Mtb+/Helm+) compared to the other groups (p < 0.05). However, there was no statistically significant difference in the CD8 median among the three participating groups (p > 0.05). Lymphopenia, monocytosis, thrombocytosis, and hypochromic microcytic anaemia were the haematological defects observed in the Mtb+/Helm+ and Mtb+/Helm- patients. Exploring these types of immune-haematological biomarkers would be a valuable aid in diagnosing and a better follow-up and monitoring of the tuberculosis-helminthiasis coinfection.

Long-term, 13-year survival after immune cell therapy combined with chemotherapy for extensive-stage small-cell lung cancer: a case report.

While the incidence of small-cell lung cancer is low, it has a poor prognosis. Patients with extensive small-cell lung cancer account for about 70% of all cases of small-cell lung cancer, with a median overall survival duration of 8-13 months and a 5-year overall survival rate of only 1%-5%. Herein, we report small-cell lung cancer diagnosed by bronchoscopic biopsy in an adult male patient in 2011. The patient had a clinical stage of cT2N2M1 and stage IV disease (i.e., extensive small-cell lung cancer). Still, he survived for 13 years through a combination of chemotherapy, radiotherapy, and cytokine-induced killer (CIK) immunocell thera. Comprehensive tumor markers, lymphocyte subsets, and lung CT images were obtained through long-term follow-up. After 12 cycles of chemotherapy (CE/IP regimen) and 5940cgy/33f radiotherapy, we found that the patient was in an immunosuppressive state, so the patient was given CIK cell therapy combined with chemotherapy. After 2 years of immunocell-combined chemotherapy, there were no significant changes in the primary lesion or other adverse events. In the 13 years since the patient's initial diagnosis, we monitored the changes in the patient's indicators such as CEA, NSE, CD4/CD8 ratio, and CD3+CD4+ lymphocytes, suggesting that these may be the factors worth evaluating regarding the patient's immune status and the effectiveness of combination therapy. In this case, CIK cell immunotherapy combined with chemotherapy was applied to control tumor progression. With a good prognosis, we concluded that CIK cell immunotherapy combined with chemotherapy can prolong patient survival in cases of extensive small-cell lung cancer, and the advantages of combined therapy are reflected in improving the body's immune capacity and enhancing the killing effect of immune cells.

Association of the pre-transplant CD4/CD8 ratio with the prognosis following allogeneic hematopoietic stem cell transplantation.

The tumor microenvironment's cells can promote or inhibit tumor formation, and there are no reports on the CD4/CD8 ratio's association with outcomes post allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively evaluated the pre-transplant peripheral blood CD4/CD8 ratio in 168 patients who underwent their first allo-HSCT for hematological malignancies at our institution. When patients were divided into two groups according to the median CD4/CD8 ratio 1.35 (range, 0.09-19.89), the high CD4/CD8 ratio group had a higher incidence of relapse, equivalent non-relapse mortality and worse overall survival (OS) than the low CD4/CD8 ratio group. In a multivariate analysis, the CD4/CD8 ratio was significantly associated with an increased risk of relapse, although there was a marginally significant difference in OS. The pre-transplant peripheral blood CD4/CD8 ratio could be a novel biomarker for predicting the prognosis of allo-HSCT.

T Cell Exhaustion Markers in Multiple Myeloma Patients are Lower After Physical Activity Intervention.

PURPOSE: There is compelling evidence that CD4+ and CD8+T cells are dysfunctional in multiple myeloma, compromising their ability to control disease progression. Pre-clinical models suggest that exercise represents a non-pharmacologic means to reduce immune exhaustion, but no studies to date have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in multiple myeloma patients. PATIENTS AND METHODS: The current study includes 24 multiple myeloma patients who participated in a six-month physical activity intervention, consisting of supervised strength training (n = 12) and unsupervised home-based walking arms (n = 12). Comprehensive flow cytometry was utilized to assess the frequency of CD4+ and CD8+T cells and subpopulations expressing the markers of exhaustion PD-1, TIGIT, TIM3 and/or LAG3. Ratios of exhausted to non-exhausted cell populations, and percentages of exhausted to total populations of the same lineage, were calculated for the baseline and final timepoints. RESULTS: Eighteen of 20 exhaustion measures were lower at the end of the intervention than at baseline, and several were significantly or borderline significantly reduced in the entire sample or in one of the arms. The entire sample saw improvements in the ratios of CD4+ TIGIT+ to non-exhausted CD4+ (0.7 [0.6] to 0.6 [0.4], P = .04) and CD8+ PD1+ to non-exhausted CD8+ (1.8 [2.6] to 1.5 [2.0], P = .06), and in total exhausted CD8+ as a percent of total CD8+ (72.9 [21.9] to 68.3 [19.6], P < .01). CONCLUSIONS: This pilot study suggests that physical activity induces changes in MM patients' immune systems, potentially rendering a less exhausted T cell state.

CD4/CD8 Ratio: An Independent Predictor of Herpes Zoster in Patients With Autoimmune Inflammatory Rheumatic Diseases.

BACKGROUND: A higher incidence of herpes zoster (HZ) was found in people with decreased cell-mediated immunity. However, the relationship between cellular immunity and HZ infection in patients with autoimmune inflammatory rheumatic diseases (AIRD) remains elusive. OBJECTIVE: To investigate the role of CD4/CD8 ratio in patients with AIRD and HZ. METHODS: This case-control study compared AIRD patients with and without HZ. We chose 70 AIRD patients with HZ as the experimental group and 140 AIRD patients without HZ as the control group. The clinical and laboratory findings were assessed in each trial participant. RESULTS: The CD4/CD8 ratio (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.10-0.49) was independently associated with the occurrence of HZ after adjusting for various confounders. Nonlinear analysis has unveiled a more profound nonlinear relationship between the CD4/CD8 ratio and the occurrence of HZ in patients with AIRD. The OR of HZ increased with a decreasing CD4/CD8 ratio before the turning point of 2. The adjusted regression coefficient was 0.14 (95% CI, 0.05-0.37, p<0.0001) for CD4/CD8 ratio less than 2. CONCLUSION: The CD4/CD8 ratio was expected to be a very promising quantitative biomarker for predicting the risk of developing HZ in patients with AIRD.

Plasma metabolomic profile is near-normal in people with HIV on long-term suppressive antiretroviral therapy.

Background: Combination antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection in people with HIV (PWH). However, a chronic state of immune activation and inflammation is maintained despite achieving HIV suppression and satisfactory immunological recovery. We aimed to determine whether the plasma metabolomic profile of PWH on long-term suppressive ART and immunologically recovered approximates the normality by comparison with healthy controls with similar age and gender. Methods: We carried out a cross-sectional study in 17 PWH on long-term ART (HIV-RNA <50 copies/mL, CD4+ ≥500 cells/mm3, and CD4+/CD8+ ≥1) and 19 healthy controls with similar age and gender. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and Generalized Linear Models (GLM) with a gamma distribution (log-link). Significance levels (p-value) were corrected for multiple testing (q-value). Results: PCA and PLS-DA analyses found no relevant differences between groups. Adjusted GLM showed 14 significant features (q-value<0.20), of which only three could be identified: lysophosphatidylcholine (LysoPC) (22:6) (q-value=0.148), lysophosphatidylethanolamine (LysoPE) (22:6) (q-value=0.050) and hydroperoxy-octadecatrienoic acid (HpOTrE)/dihydroperoxy-octadecatrienoic acid (DiHOTrE)/epoxy-octadecadienoic acid (EpODE) (q-value=0.136). These significant identified metabolites were directly correlated to plasma inflammatory biomarkers in PWH and negatively correlated in healthy controls. Conclusion: PWH on long-term ART have a metabolomic profile that is almost normal compared to healthy controls. Nevertheless, residual metabolic alterations linked to inflammatory biomarkers persist, which could favor the development of age-related comorbidities among this population.

Corrigendum: CD4/CD8 ratio and CD8+ T-cell count as prognostic markers for non-AIDS mortality in people living with HIV. A systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fimmu.2024.1343124.].

Does excess body weight accelerate immune aging?

BACKGROUND: Overweight and obesity in older adults increase the risk of a range of comorbidities by sustaining chronic inflammation and thus enhancing immunosenescence. This study aimed to assess whether excess body mass affected disproportion in T lymphocytes. Therefore, the study was designed to explain whether excess body mass in older individuals affected the disproportion in numbers of T lymphocytes and whether anthropometric indices and immune risk profile expressed as CD4/CD8 ratio are diagnostically useful in the analysis of immunosenescence. MATERIALS & METHODS: One hundred three individuals aged 73.6 ± 3.1 years were allocated to the normal body mass (body mass index (BMI) 18.5-24.9 kg/m2,n = 39), the pre-obesity (BMI 25.0-29.9 kg/m2, n = 44) or the obesity (BMI ≥30.0 kg/m2, n = 20) group, based on WHO recommendations. Details on the subjects' medical history and lifestyle were obtained by health questionnaire. Anthropometric analysis was performed by bioelectrical impedance method, biochemical analysis was made by the automatic analyzer and ELISA immunoassays, and T and B lymphocyte counts were determined by eight-parameter flow cytometry. Additionally, visceral adiposity index, body adiposity index (BAI), and body shape index (ABSI) were evaluated based on body circumference, BMI and lipid-lipoprotein profile measurements. RESULTS: The highest percentage of CD3+CD4+ T lymphocytes (59.4 ± 12.6 %) and the lowest CD3+CD8+ T lymphocytes (31.6 ± 10.0 %) were noted in patients the obesity group. The highest cut-off value of 1.9 for CD4/CD8 ratio was recorded in the normal body mass vs pre-obesity model. CD4/CD8 ratio > 2.5 was recorded in >20 % of our pre-obesity and obesity groups while 64.5 % of the normal body mass group had CD4/CD8 ratio < 1. High diagnostic usefulness was demonstrated for both BAI and lipid accumulation product (LAP) (AUC values of ~0.800 and ~ 0.900 respectively) in three models: normal body mass vs pre-obesity, normal body mass vs obesity, and pre-obesity vs obesity. CONCLUSION: The odds ratios (OR) for CD4/CD8 ratio in the normal body mass vs obesity model (OR = 16.1, 95%CI 3.8-93.6) indicated a potential diagnostic value of T lymphocytes for clinical prognosis of immune aging in relation to excess body weight in older adults. High values of AUC obtained for the following models: CD4/CD8 + BAI (AUC = 0.927), CD4/CD8 + LAP (AUC = 1.00), CD4/CD8 + ABSI (AUC = 0.865) proved to provide excellent discrimination between older adults with obesity and with normal body mass.

CD4/CD8 ratio and CD8+ T-cell count as prognostic markers for non-AIDS mortality in people living with HIV. A systematic review and meta-analysis.

Background: In people living with HIV (PLHIV), the CD4/CD8 ratio has been proposed as a useful marker for non-AIDS events. However, its predictive ability on mortality over CD4 counts, and the role of CD8+ T-cell counts remain controversial. Methods: We conducted a systematic review and meta-analysis of published studies from 1996 to 2023, including PLHIV on antiretroviral treatment, and reporting CD4/CD8 ratio or CD8+ counts. The primary outcome was non-AIDS mortality or all-cause mortality. We performed a standard random-effects pairwise meta-analysis comparing low versus high CD4/CD8 ratio with a predefined cut-off point of 0.5. (CRD42020170931). Findings: We identified 2,479 studies for screening. 20 studies were included in the systematic review. Seven studies found an association between low CD4/CD8 ratio categories and increased mortality risk, with variable cut-off points between 0.4-1. Four studies were selected for meta-analysis, including 12,893 participants and 618 reported deaths. Patients with values of CD4/CD8 ratio below 0.5 showed a higher mortality risk (OR 3.65; 95% CI 3.04 - 4.35; I2 = 0.00%) compared to those with higher values. While the meta-analysis of CD8+ T-cell counts was not feasible due to methodological differences between studies, the systematic review suggests a negative prognostic impact of higher values (>1,138 to 1,500 cells/uL) in the long term. Conclusions: Our results support the use of the CD4/CD8 ratio as a prognostic marker in clinical practice, especially in patients with values below 0.5, but consensus criteria on ratio timing measurement, cut-off values, and time to event are needed in future studies to get more robust conclusions. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020170931, identifier CRD42020170931.

Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a "gold-standard" as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance. METHODS: Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53-/- and KrasLSL-G12D/+p53LSL-R172H/+, respectively). RESULTS: The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+ and CD8+ T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors. CONCLUSIONS: Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.

The Association of HIV-Specific Risk Factors with Cardiovascular Events in Addition to Traditional Risk Factors in People Living with HIV.

Traditional cardiovascular risk scores underestimate the incidence of cardiovascular diseases (CVD) in people living with HIV (PLH). This study compared the effect of HIV-specific cardiovascular risk factors (CRF) with traditional CRF at baseline for their association with incident CVD in PLH. The ongoing, prospective HIV HEART Aging (HIVH) study assesses CVD in PLH in the German Ruhr Area since 2004. PLH from the HIVH study with at least 5 years of follow-up were examined with the help of Cox proportional hazards models using inverse probability-of-censoring weights. The models were adjusted for age and sex. The obtained hazard ratios (HR) and 95% confidence limits (CL) assessed the strength of the associations between CRF and CVD. One thousand two hundred forty-three individuals (male 1,040, female 203; mean age of 43 ± 10 years) with 116 incident CVD events were analyzed. After adjusting for the traditional CRF, the HIV-specific CRF "a history of AIDS" and "higher age at diagnosis of HIV infection" (per 10 years) were associated with an increased CVD risk (HR 1.55, 95% CL: 1.05-2.28 and HR 1.55, 95% CL: 1.09-1.22, respectively). Higher CD4/CD8 ratio (per standard deviation), longer cumulative duration of antiretroviral therapies, and longer duration of HIV infection (per 10 years) showed indications for a decreased CVD risk (HR 0.75, 95% CL: 0.58-0.97, HR 0.71, 95% CL: 0.41-1.23, and HR 0.63, 95% CL: 0.44-0.90, respectively). Out of the traditional CRF, current smoking showed the strongest impact on CVD risk (HR 3.12, 95% CL: 2.06-4.74). In conclusion, HIV-specific factors, such as history of AIDS and CD4/CD8 ratio, were independently associated with an increased cardiovascular risk. Traditional CRF maintained a major effect on CVD. Clinical Trials Number (NCT04330287).

Measures of Longitudinal Immune Dysfunction and Risk of AIDS and Non-AIDS Defining Malignancies in Antiretroviral-Treated People With Human Immunodeficiency Virus.

BACKGROUND: Human immunodeficiency virus (HIV) infection leads to chronic immune activation/inflammation that can persist in virally suppressed persons on fully active antiretroviral therapy (ART) and increase risk of malignancies. The prognostic role of low CD4:CD8 ratio and elevated CD8 cell counts on the risk of cancer remains unclear. METHODS: We investigated the association of CD4:CD8 ratio on the hazard of non-AIDS defining malignancy (NADM), AIDS-defining malignancy (ADM) and most frequent group of cancers in ART-treated people with HIV (PWH) with a CD4 and CD8 cell counts and viral load measurements at baseline. We developed Cox proportional hazard models with adjustment for known confounders of cancer risk and time-dependent cumulative and lagged exposures of CD4:CD8 ratio to account for time-evolving risk factors and avoid reverse causality. RESULTS: CD4:CD8 ratios below 0.5, compared to above 1.0, were independently associated with a 12-month time-lagged higher risk of ADM and infection-related malignancies (adjusted hazard ratio 2.61 [95% confidence interval {CI }1.10-6.19] and 2.03 [95% CI 1.24-3.33], respectively). CD4 cell counts below 350 cells/µL were associated with an increased risk of NADMs and ADMs, as did infection, smoking, and body mass index-related malignancies. CONCLUSIONS: In ART-treated PWH low CD4:CD8 ratios were associated with ADM and infection-related cancers independently from CD4 and CD8 cell counts and may alert clinicians for cancer screening and prevention of NADM.

Relationship Between Peripheral Blood T Lymphocyte Subsets and Prognosis of Patients with Advanced Non-small Cell Lung Cancer Treated with Camrelizumab / 肿瘤防治研究

Objective To explore the relationship between peripheral blood T lymphocyte subsets and prognosis of patients with advanced non-small cell lung cancer (NSCLC) who received treatment with camrelizumab. Methods We retrospectively collected data from 88 patients with advanced NSCLC who underwent camrelizumab treatment. Peripheral blood lymphocyte subsets were collected from patients before and two months after treatment. Kaplan-Meier curves and Cox regression analysis were employed to investigate the relationship between peripheral blood T lymphocyte subsets and PFS and OS. Results Compared with non-responder group, the baseline peripheral blood CD4+/CD8+ ratio was higher (P=0.038), while the CD8+T lymphocyte percentage was lower (P=0.036) in the responder group. Kaplan-Meier curves showed that a high baseline CD4+/CD8+ ratio was associated with long PFS and OS (P=0.001, P=0.023). Multivariate Cox analysis revealed that the baseline CD4+/CD8+ ratio was a significant predictor for PFS and OS. Additionally, a high post-treatment CD4+/CD8+ ratio and high CD4+T lymphocyte percentage were associated with long PFS (P=0.005, P=0.015), whereas a low post-treatment CD8+T lymphocyte percentage was associated with long PFS and OS (P=0.001, P=0.016). Conclusion The peripheral blood CD4+/CD8+ ratio can serve as a predictive factor for survival of patients with NSCLC treated with camrelizumab.