Review Article
Yuyu Xu; Huiling Shen
Abstract
Immune checkpoint inhibitors have revolutionized cancer therapy by delivering long-lasting responses in a subset of patients across many cancer types. Yet, their effectiveness is often limited by high rates of primary and acquired resistance. This resistance is driven by complex interactions among tumor-intrinsic ...
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Immune checkpoint inhibitors have revolutionized cancer therapy by delivering long-lasting responses in a subset of patients across many cancer types. Yet, their effectiveness is often limited by high rates of primary and acquired resistance. This resistance is driven by complex interactions among tumor-intrinsic alterations, immunosuppressive factors within the tumor microenvironment, and host-related determinants. This review critically examines the biological mechanisms underlying resistance to immune checkpoint inhibitors, including defects in antigen presentation, dysregulated interferon signaling, activation of oncogenic pathways, compensatory upregulation of alternative immune checkpoints, and microbiome-associated immune modulation. In addition to defining these challenges, this review also highlights emerging opportunities for overcoming these obstacles. Emerging opportunities to circumvent resistance include biomarker-guided patient stratification, rational combination therapies that engage complementary immune pathways, modulation of the tumor microenvironment, and integration of multi-omics approaches to identify predictive resistance signatures. The central conclusion of this review is that effective clinical translation will necessitate a paradigm shift from discrete pathway inhibition toward integrated precision immuno-oncology strategies that combine molecular profiling, immune-contexture analysis, and mechanism-based combination therapies. Such integrated approaches may improve patient selection, overcome resistance, and expand the proportion of patients who achieve durable responses to immune checkpoint blockade.
Short Communication
Nasrin Sereshki; Razieh Alipour; Nahid Rezaei; Abbas Rezaei; Mohsen Naseri; Fahimeh Ghasemi; Seyedeh Sindokht Hosseini; Mitra Rafiee
Abstract
Background: Pregnancy is a unique immunological state in which the semi-allogeneic fetus must be tolerated by the maternal immune system. Progesterone-induced blocking factor (PIBF) contributes to sustaining this immune balance through its regulatory effects, particularly those involving CD25⁺ T cells ...
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Background: Pregnancy is a unique immunological state in which the semi-allogeneic fetus must be tolerated by the maternal immune system. Progesterone-induced blocking factor (PIBF) contributes to sustaining this immune balance through its regulatory effects, particularly those involving CD25⁺ T cells and maternal immune tolerance mechanisms.
Objective: To investigate whether PIBF influences the proportion of Foxp3+ cells among activated human peripheral CD4+ CD25+ T cells.
Materials and methods: We isolated peripheral blood mononuclear cells (PBMCs) were isolated from 15 healthy women of reproductive-age, all sampled during the follicular phase of their menstrual cycles. The cells were stimulated with anti-CD3, anti-CD28 and IL-2 and cultured for 5 days in the presence or absence of PIBF at concentrations of 200 or 1000 ng/mL. The proportion of CD4+CD25+Foxp3+T cells was quantified by flow cytometry.
Results: Treatment with PIBF increased the percentage of CD4+CD25+Foxp3+ T cells compared with untreated controls (mean ± SE: control 2.7 ± 1.18%; PIBF 200 ng/mL 3.05 ± 1.06%, p = 0.008; PIBF 1000 ng/mL 3.50 ± 1.39%, p = 0.002). Although the increases were significant relative to the control group, no clear dose‑dependent trend was observed between the two PIBF concentrations. No adverse effects on cell viability were detected under the experimental conditions.
Conclusion: In vitro treatment of activated human peripheral CD4+CD25+ T cells with PIBF increased the percentage of Foxp3+ cells, suggesting that PIBF may promote regulatory T cell phenotypes in the context of maternal–fetal tolerance.
