Prognostic value of T-cells between primary colorectal cancer (pCRC) and its paired synchronous and metachronous liver metastasis (LM) is underinvestigated and is the subject of the present study. We enrolled into this retrospective cohort study patients, who underwent resection of both pCRC and synchronous LM (N = 55) or metachronous LM (N = 44). After immunohistochemical staining for CD3+, CD8+, and CD45R0+ whole slides were scanned and T-cell densities were quantified using QuPath software in tumor center (TC), inner margin (IM), outer margin (OM), and peritumor zone (PT) of pCRC and LM. High densities of CD8+ T-cells in TC, OM and PT of synchronous LM were associated with longer disease-free survival (DFS). Greater densities of CD3+ T-cells in IM and PT and CD8+ T-cells in IM, OM and PT in synchronous LM over pCRC were associated with longer DFS. Greater densities of CD8+ T-cells in the TC and IM and CD3+ T-cells in the IM of pCRC were found in the metachronous over synchronous group. The first novel finding demonstrated that high density of CD8+ T cells in synchronous LM were associated with favorable outcome. The second finding of high CD8+ cell density in pCRC in metachronous over synchronous CRC may provide a mechanistic basis for the delay of metastatic spread. Both findings could be applied clinically with own reference values.

• MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Adult MeSH
• Colorectal Neoplasms * pathology   immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasms, Multiple Primary pathology   immunology   MeSH
• Liver Neoplasms * secondary   immunology   pathology   MeSH
• Disease-Free Survival MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Neoplasms, Second Primary pathology   MeSH
• Aged MeSH
• T-Lymphocytes immunology   pathology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   pathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.

• MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Tumor-Associated Macrophages immunology   MeSH
• Tumor Microenvironment * immunology   MeSH
• Prostatic Neoplasms * immunology   pathology   therapy   MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Our aim is to determine the number of leukocytes, T lymphocytes and B lymphocytes and the expression of activation markers CD200 and CD23 on B lymphocytes in atopic dermatitis (AD) patients (treated and not treated with dupilumab) during the pollen season. We examined 29 patients not treated with dupilumab, 24 patients treated with dupilumab and 40 healthy subjects as a control group. The count of T and B lymphocytes and their subsets were assessed by flow cytometry. The non-parametric Kruskal-Wallis one-factor analysis of variance with post hoc by Dunn's test with Bonferroni's modification was used for statistical processing. Although there was a significant improvement in skin findings in patients treated with dupilumab, the changes in immunological profile show a persistent altered immune response characterized by dysregulation and overactivation of B lymphocytes. Dupilumab therapy leads to normalization of relative T regulatory lymphocytes and total memory B lymphocytes and to decreased count of absolute CD8+ T lymphocytes. Why carry out this study?Studies investigating the immunological profile of atopic dermatitis (AD) patients during the pollen season are rare. There are no studies investigating the count of B lymphocytes (CD5+, CD22+ and CD73+ B lymphocytes) and the expression of activation markers CD23 and CD200 on B lymphocytes and on their subsets during pollen season in AD patients treated and non-treated with dupilumab therapy.What was learned from the study?In atopic dermatitis (AD) patients with and without dupilumab therapy, we confirmed the significantly higher count of absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, non-switched B lymphocytes, transitional B lymphocytes, CD23 memory, naive, non-switched, switched and total CD23 B lymphocytes, the relative count of CD200 memory and CD200 switched B lymphocytes.In dupilumab treated patients, we confirmed the significantly higher count of relative eosinophils, relative CD16+ eosinophils, relative CD200 non-switched B lymphocytes and lower count of absolute CD8+ T lymphocytes. Further studies should focus on investigating the effect of dupilumab on CD8+ T lymphocytes and their subpopulations.In patients without dupilumab therapy, we confirmed the significantly higher count of relative neutrophils, relative T regulatory lymphocytes and total memory B lymphocytes.The changes in the count of CD5+, CD22+ and CD73+ B lymphocytes were not observed during pollen season in both groups of AD patients.

• MeSH
• Dermatitis, Atopic * drug therapy   immunology   MeSH
• B-Lymphocytes immunology   MeSH
• Antigens, CD MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pollen immunology   MeSH
• Receptors, IgE MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: The aim of the study was the assessment of adherence to antiretroviral (ARV) treatment in a population of people living with HIV (PWH), improving the awareness of PWH, drawing attention to the risk of developing HIV drug resistance and subsequent treatment failure. METHODS: The basic cohort consisted of PWH followed up long-term at the HIV centre of the University Hospital Pilsen. Adherence to treatment was assessed by ARV levels. Nucleoside analogs were determined in urine by high pressure liquid chromatography (HPLC), in relation to clinical data, viral load (HIV RNA), and absolute CD4 and CD8 T cell counts. To assess mental and physical state of the patients, a modified SF-36 questionnaire was used to measure social relationships, education and ability to relax. RESULTS: From a group of 131 PWH, 18 (13.7%) with zero levels and 113 (86.3%) with any detectable ARV levels were followed for 6-12 months. A statistically significant lower viral load was demonstrated in patients who adhered to the treatment at the time of the test as indicated by ARV levels in the urine. CD4 T lymphocyte values in adherent patients were, as expected, statistically significantly higher. A significant difference for CD8 T lymphocyte was not demonstrated. A survey assessed subjective factors influencing the degree of adherence. PWH consider important: quality care enabling trust, low risk of developing opportunistic infections, self-sufficiency, quality of sleep, managing leisure activities, and good family relationships. Quality of life evaluation and satisfaction in the monitored areas were similar in both groups of PWH. CONCLUSIONS: Non-adherence leads to deterioration of CD4 and viral load levels and may be the cause of the development of HIV drug resistance and treatment failure on the part of the patient. PWH with zero or low urinary nucleoside levels were repeatedly instructed about the need for regular and sustained medication use. Regular checks with a laboratory examination service are needed to detect early emergence of resistance and side effects of the treatment, which are initially only detectable in the laboratory.

• MeSH
• Medication Adherence * psychology   MeSH
• Adult MeSH
• HIV Infections * drug therapy   psychology   MeSH
• Cohort Studies MeSH
• Quality of Life * MeSH
• Anti-HIV Agents * therapeutic use   urine   MeSH
• Middle Aged MeSH
• Humans MeSH
• CD4 Lymphocyte Count MeSH
• Viral Load MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: SOT201 and its murine surrogate mSOT201 are novel cis-acting immunocytokines consisting of a humanized/murinized/, Fc-silenced anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) fused to an attenuated human interleukin (IL)-15 and the IL-15Rα sushi+ domain. Murine mPD1-IL2v is a conjugate of a murinized, Fc silenced anti-PD-1 mAb bearing human IL-2 with abolished IL-2Rα binding. These immunocytokines spatiotemporally reinvigorate PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs) via cis-activation and concomitantly activate the innate immunity via IL-2/15Rβγ signaling. METHODS: Human peripheral blood mononuclear cell and cell lines were used to evaluate cis/trans activity of SOT201. Anti-PD-1 mAb responsive (MC38, CT26) and resistant (B16F10, CT26 STK11 KO) mouse tumor models were used to determine the anticancer efficacy, and the underlying immune cell activity was analyzed via single-cell RNA sequencing and flow cytometry. The expansion of tumor antigen-specific CD8+ T cells by mSOT201 or mPD1-IL2v and memory CD8+ T-cell generation in vivo was determined by flow cytometry. RESULTS: SOT201 delivers attenuated IL-15 to PD-1+ T cells via cis-presentation, reinvigorates exhausted human T cells and induces higher interferon-γ production than pembrolizumab in vitro. mSOT201 administered as a single dose exhibits strong antitumor efficacy with several complete responses in all tested mouse tumor models. While mPD1-IL2v activates CD8+ T cells with a 50-fold higher potency than mSOT201 in vitro, mSOT201 more effectively reactivates effector exhausted CD8+ T cells (Tex), which demonstrate higher cytotoxicity, lower exhaustion and lower immune checkpoint transcriptional signatures in comparison to mPD1-IL2v in MC38 tumors in vivo. This can be correlated with a higher rate of complete responses in the MC38 tumor model following mSOT201 treatment when compared with mPD1-IL2v. mSOT201 increased the relative number of tumor antigen-specific CD8+ T cells, and unlike mPD1-IL2v stimulated greater expansion of adoptively transferred ovalbumin-primed CD8+ T cells simultaneously limiting the peripheral CD8+ T-cell sink, leading to the development of memory CD8+ T cells in vivo. CONCLUSIONS: SOT201 represents a promising therapeutic candidate that preferentially targets PD-1+ TILs, delivering balanced cytokine activity for reviving CD8+ Tex cells in tumors. SOT201 is currently being evaluated in the Phase I clinical study VICTORIA-01 (NCT06163391) in patients with advanced metastatic cancer.

• MeSH
• Programmed Cell Death 1 Receptor * antagonists & inhibitors   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Immune Checkpoint Inhibitors pharmacology   MeSH
• Interleukin-15 * genetics   pharmacology   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: The efficacy of anti-CD20 antibodies has significantly contributed to advancing our understanding of disease pathogenesis and improved treatment outcomes in relapsing-remitting multiple sclerosis (RRMS). A comprehensive analysis of the peripheral immune cell profile, combined with prospective clinical characterization, of RRMS patients treated with ocrelizumab (OCR) or ofatumumab (OFA) was performed to further understand immune reconstitution following B-cell depletion. METHODS: REBELLION-MS is a longitudinal analysis of RRMS patients treated with either OCR (n = 34) or OFA (n = 25). Analysis of B, T, natural killer (NK) and natural killer T (NKT) cells at baseline, month 1, and 12 was performed by multidimensional flow cytometry. Data were analyzed by conventional gating and unsupervised computational approaches. In parallel, different clinical parameters were longitudinally assessed. Twenty treatment-naïve age/sex-matched RRMS patients were included as the control cohort. RESULTS: B-cell depletion by OCR and OFA resulted in significant reductions in CD20+ T and B cells as well as B-cell subsets, alongside an expansion of CD5+CD19+CD20- B cells, while also elevating exhaustion markers (CTLA-4, PD-1, TIGIT, TIM-3) across T, B, NK, and NKT cells. Additionally, regulatory T-cell (TREG) numbers increased, especially in OCR-treated patients, and reductions in double-negative (CD3+CD4-CD8-) T cells (DN T cells) were observed, with these DN T cells having higher CD20 expression compared to CD4 or CD8 positive T cells. These immune profile changes correlated with clinical parameters, suggesting pathophysiological relevance in RRMS. CONCLUSIONS: Our interim data add weight to the argumentation that the exhaustion/activation markers, notably TIGIT, may be relevant to the pathogenesis of MS. In addition, we identify a potentially interesting increase in the expression of CD5+ on B cells. Finally, we identified a population of double-negative T cells (KLRG1+HLADR+, in particular) that is associated with MS activity and decreased with CD20 depletion.

• MeSH
• Antigens, CD20 * immunology   MeSH
• B-Lymphocytes immunology   drug effects   MeSH
• Killer Cells, Natural immunology   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Multiple Sclerosis, Relapsing-Remitting * immunology   drug therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Antisense transcripts play an important role in generating regulatory non-coding RNAs but whether these transcripts are also translated to generate functional peptides remains poorly understood. In this study, RNA sequencing and six-frame database generation were combined with mass spectrometry analysis of peptides isolated from polysomes to identify Nascent Pioneer Translation Products (Na-PTPs) originating from alternative reading frames of bi-directional transcripts. Two Na-PTP originating peptides derived from antisense strands stimulated CD8+ T cell proliferation when presented to peripheral blood mononuclear cells (PBMCs) from nine healthy donors. Importantly, an antigenic peptide derived from the reverse strand of two cDNA constructs was presented on MHC-I molecules and induced CD8+ T cell activation. The results demonstrate that three-frame translation of bi-directional transcripts generates antigenic peptide substrates for the immune system. This discovery holds significance for understanding the origin of self-discriminating peptide substrates for the major histocompatibility class I (MHC-I) pathway and for enhancing immune-based therapies against infected or transformed cells.

• MeSH
• Lymphocyte Activation immunology   MeSH
• RNA, Antisense * genetics   immunology   MeSH
• CD8-Positive T-Lymphocytes * immunology   MeSH
• Leukocytes, Mononuclear immunology   MeSH
• Humans MeSH
• Histocompatibility Antigens Class I * immunology   genetics   MeSH
• Peptides * immunology   genetics   MeSH
• Antigen Presentation MeSH
• Protein Biosynthesis * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

• MeSH
• B7-H1 Antigen * antagonists & inhibitors   metabolism   immunology   MeSH
• CD8-Positive T-Lymphocytes immunology   MeSH
• Immunotherapy methods   MeSH
• Immune Checkpoint Inhibitors * pharmacology   therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Neoplasms immunology   radiotherapy   therapy   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Intestines pathology   radiation effects   MeSH
• Gastrointestinal Microbiome MeSH
• Animals MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

• MeSH
• Killer Cells, Natural * immunology   metabolism   drug effects   MeSH
• DNA Helicases * metabolism   genetics   MeSH
• Nuclear Proteins * metabolism   genetics   MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Ovarian Neoplasms drug therapy   metabolism   pathology   genetics   immunology   MeSH
• Signal Transduction drug effects   MeSH
• Cellular Senescence * drug effects   MeSH
• Transcription Factors * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-Positive T-Lymphocytes * immunology   drug effects   MeSH
• Tertiary Lymphoid Structures * immunology   pathology   MeSH
• Hepatocyte Nuclear Factor 1-alpha * genetics   metabolism   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Carboplatin administration & dosage   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   drug effects   MeSH
• Ovarian Neoplasms * drug therapy   immunology   pathology   MeSH
• Neoadjuvant Therapy methods   MeSH
• Paclitaxel administration & dosage   therapeutic use   pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   pharmacology   MeSH
• Cystadenocarcinoma, Serous drug therapy   pathology   immunology   MeSH
• Endoplasmic Reticulum Stress drug effects   immunology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   drug effects   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH