Journal of Immunotherapy最新文献

This study aimed to assess factors associated with overall survival (OS) in patients with microsatellite stable (MSS) stage IV rectal cancer treated with immunotherapy. In this retrospective review of the NCDB (2015-2021), patients with MSS stage IV rectal adenocarcinoma were divided into immunotherapy and control groups, and propensity-score matched and compared. Multivariable Cox regression analysis was performed to assess the effect of immunotherapy and KRAS genotype on OS. Of 6489 included patients (64.6% males), immunotherapy was given to 47.9%. After matching for age, insurance type, liver metastases, surgery, radiation therapy, and chemotherapy, there were 2422 patients in each group. In the matched cohort, immunotherapy was associated with a similar median OS to the control group [31.8 (95% CI: 27.8-32.2) months vs 29.7 (95% CI: 27.8-32.2) months, P = 0.062]. Immunotherapy was not independently associated with improved OS (HR: 0.88, 95% CI: 0.69-1.14, P = 0.341) but was associated with longer median OS in black patients (25.8 vs 19.1 mo, P = 0.019), patients with bone metastases (22.1 vs 10.7, P < 0.001) and with KRAS mutation (27.4 vs 24.3 mo, P = 0.003). There was no survival benefit from immunotherapy when combined with radical resection, radiation therapy, or chemotherapy. In conclusion, immunotherapy was associated with a modest increase in OS of MSS stage IV rectal cancers, but not independently associated with improved survival. Black patients with bone metastases and KRAS mutations may have survival benefit from immunotherapy. Increased OS with immunotherapy was noted only in patients who did not have surgery, radiation, or chemotherapy. These results seem somewhat disappointing given the enthusiasm for immunotherapy.

Abstract: Kaposi Sarcoma (KS) is an angioproliferative tumor induced by human gammaherpesvirus 8 (HHV-8). For years, cytotoxic chemotherapy was the primary treatment for advanced KS, despite high toxicity and limited efficacy. Immunotherapy, particularly PD-1/PD-L1 inhibitors, has emerged as a promising option with antitumor activity and a favorable safety profile. We conducted a meta-analysis to evaluate its efficacy and safety in KS. A systematic search in Medline, Embase, Cochrane Library, and Web of Science identified single-arm trials on PD-1/PD-L1 inhibitors in KS. Outcomes were expressed as proportions with 95% CIs, heterogeneity assessed using I ², and significance set at P <0.05. Analyses were performed in RStudio 4.4.1. Five studies with 91 patients were included. Prior treatments included chemotherapy (35.0%), radiotherapy (22.3%), and interferon (9.2%). The pooled objective response rate (ORR) was 61% (95% CI: 49-72; I ²=16%), with 17% achieving complete response (CR) (95% CI: 8-31; I ²=0%), and the disease control rate (DCR) was 91% (95% CI: 81-96; I ²=0%). The most frequent adverse events (AEs) were pruritus (42%; 95% CI: 16-73; I ²=74%), fatigue (27%; 95% CI: 8-60; I ²=67%), and arthralgia (14%; 95% CI: 5-37; I ²=60%). This meta-analysis supports the antitumor activity of PD-1/PD-L1 inhibitors in KS. Despite high AE rates, most were clinically manageable.

Cold tumors have an immunosuppressive microenvironment (TME) with weak infiltration of functionally active NK and T cells. Such tumors poorly respond to immunotherapies, and different combined approaches are investigated to reprogram cold tumors into hot ones and improve treatment efficacy. The search for novel immunostimulatory factors for the therapy of cold tumors is of particular clinical relevance. Previously, we showed the antitumor effects of recombinant human Cyclophilin A (rhCypA), an analog of proinflammatory secretory CypA, in experimental models in vivo and indicated it as a stimulator of the antitumor immune response and a modulator of the immune TME. In this study, the effect of rhCypA on the functionality of tumor-infiltrating NK and T cells was investigated using the melanoma B16 tumor model in vivo . After rhCypA treatment, T cells in the TME differently expressed the transcription factors Tbet and Eomes and the exhaustion markers PD-1, LAG-3, and TIM3. Tumors of rhCypA-dosed mice contained a higher proportion of activated CD4 + CD25 + T cells and CD8 + T cells with upregulated activation markers CD44 and CD25 and co-stimulatory CD28. Similarly, rhCypA upregulated PD-1, CTLA-4, and CD25 and downregulated exhaustion markers KLRG-1 and LAG-3 in tumor-infiltrating NK cells. After rhCypA treatment, melanoma B16 was actively infiltrated with CD8 + T cells and NK cells with increased perforin and granzyme B production and TNFα-producing CD4 + cells. Thus, rhCypA reprogrammed the immune tumor microenvironment by boosting the accumulation of functionally more active NK and T cells with the enhanced production of cytotoxic factors while modulating their dysfunction and weakening immunosuppression.

To explore the relationship between early dynamic changes in neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) and treatment outcomes of patients with advanced nonsmall cell lung cancer (NSCLC) undergoing immunotherapy, we retrospectively analyzed 217 advanced NSCLC patients who received immunotherapy. NLR and LMR at baseline and 3 weeks after initiation of treatment and changes of NLR and LMR were calculated. Univariate and multivariable COX regression analysis was applied to explore the predictors of overall survival (OS). One hundred six (48.8%) demonstrated an increase in NLR after 3 weeks of initiating treatment, while 111 (51.2%) displayed a decrease in NLR. Low pretreatment and post-treatment NLR levels (<5), high pretreatment and post-treatment LMR levels (≥4), reduction of post-treatment NLR and elevation of post-treatment LMR were associated with improved objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and OS. In multivariate regression analysis, the number of distant metastases, lines of immunotherapy, levels of pretreatment and post-treatment NLR and LMR were significantly associated with OS. We developed the "NLML" prognostic scoring system, which showed an area under the curve (AUC) of 0.775 (95% CI: 0.700-0.838, P <0.001) and reached its peak at 3 years (AUC=0.955, 95% CI: 0.909-0.982, P <0.001). Early dynamic alterations in NLR and LMR values from pre-treatment to post-treatment, along with individual pretreatment or post-treatment NLR or LMR levels, exhibited correlations with treatment outcomes in patients undergoing either mono-immunotherapy or chemoimmunotherapy. The "NLML" prognostic scoring system emerged as a practical and effective model for predicting survival within this patient population.

The present study was designed to evaluate the efficacy and safety of induction chemotherapy combined with a PD-1 inhibitor (sintilimab) followed by concurrent chemoradiotherapy (CCRT) plus sintilimab and subsequent maintenance (IC-ICCRT-IO) in patients with unresectable locally advanced esophageal squamous carcinoma (ESCC) compared with induction chemotherapy followed by CCRT without PD-1 inhibitors (CT-CCRT) using propensity score matching (PSM). Data collected from patients with histologically confirmed, inoperable ESCC treated with IC-ICCRT-IO or CT-CCRT were retrospectively analyzed-a 1:1 PSM with a caliper of 0.05 balanced potential biases. Treatment effects and adverse events (AEs) were assessed using imaging, medical records, and follow-up. Primary endpoints were median progression-free survival (PFS) and PFS rates at 12 and 18 months. Secondary endpoints included overall survival (OS), response rates, and safety. The results showed that t he PSM produced 27 comparable pairs; the median follow-up was 20.5 months. IC-ICCRT-IO significantly improved PFS (median not reached, 12 mo rate: 96.6% vs. 80.5%; 18 mo rate: 85.2% vs. 63.0%, P =0.011) and OS (median not reached, 12 and 18 mo rate: 100% vs. 88.9%, P =0.007). Objective response rates were 88.9% versus 48.1% ( P =0.003). Grade ≥3 AEs occurred in 55.6% versus 44.4% ( P =0.586), primarily nonimmune-related. Severe immune-related rash and radiation pneumonitis were rare and manageable. The results suggested that IC-ICCRT-IO shows promise as an effective, safe treatment for unresectable, locally advanced ESCC. Prospective studies are needed to confirm these findings.

Abstract: Triple-negative breast cancers (TNBCs), especially metastatic recurrent TNBCs, have a poorer prognosis than many other breast cancers. In recent years, immunotherapy using immune checkpoint inhibitors has been conducted for TNBC patients. Although a limited proportion of patients show excellent response, about half of the patients do not significantly respond to the immunotherapy. Monocytes are the progenitors of macrophages that are most abundantly seen in the tumor microenvironment (TME), but the influence of monocytes on breast cancer cells (BCCs) has not been fully clarified. Thus, we examined whether monocytes prompted BCCs to express PD-L1. As results, BCCs expressed higher levels of PD-L1 and its mRNA after co-culture with monocytes. RNA sequencing analysis revealed overexpression of Moesin mRNA in the BCCs co-cultured with monocytes. siRNA-mediated knockdown of Moesin restored the increase in PD-L1 expression. An addition of CD44 antibody canceled the augmentation of PD-L1 expression caused by the co-culture, suggesting that Moesin and CD44 may be essentially involved in the cell-to-cell interaction between monocytes and BCCs to induce PD-L1 expression. These findings may suggest a novel machinery of tumor escape from anti-tumor immunity, potentially providing implications for improving immunotherapy against TNBCs that are resistant to current immune checkpoint blockade therapy.

DLGAP5 has emerged as a potential biomarker implicated in tumor progression across various cancers, yet its prognostic value in lung cancer remains to be fully elucidated. In this study, we integrated comprehensive bioinformatics analyses with clinical data to investigate the expression patterns of DLGAP5 and its association with patient outcomes in lung cancer. Expression profiling revealed that DLGAP5 levels varied modestly across clinical subgroups defined by age, sex, tumor stage, and grade, with no statistically significant differences observed. Survival analyses demonstrated that elevated DLGAP5 expression was significantly correlated with reduced overall survival, while disease-free survival showed no marked difference. Multivariate Cox regression and clinical prognostic models further confirmed DLGAP5 as an independent risk factor associated with poorer prognosis (HR=2.35, 95% CI: 1.10-5.03, P=0.021). Functional enrichment analyses of differentially expressed genes between the low-DLGAP5 expression group and high-DLGAP5 expression group identified key biological processes and pathways, including transcriptional regulation and cytoskeletal organization, potentially mediating DLGAP5's role in lung cancer progression. These findings provide robust evidence supporting the prognostic relevance of DLGAP5 in lung cancer and underscore its potential utility as a therapeutic target.

Persistent infections with high-risk human papillomavirus (HR-HPV) are the primary cause of vaginal/cervical squamous intraepithelial neoplasia (VAIN/CIN) and cervical cancer (CC), with the prevalence of infection escalating alongside disease severity. Notably, the α-9 HPV species was responsible for 58.20% of all HR-HPV infections in our study. Given the absence of therapies to eradicate established infections, developing effective therapeutic vaccines is a critical priority. The HPV E6 oncoprotein represents an ideal target for such immunotherapies. In this study, we used a comprehensive in silico approach to identify and characterize potential T-lymphocyte epitopes from the E6 proteins of α-9 HR-HPV, which was predominant in our study cohort. Our integrated bioinformatics pipeline encompassed sequence analysis for conservation, followed by rigorous prediction of antigenicity, allergenicity, proteasomal processing, TAP transport efficiency, and immunogenicity. Through this systematic screening, we identified a panel of epitope candidates predicted to have a high potential for eliciting a robust and specific immune response. While these predictions provide a powerful theoretical foundation, it must be stressed that they constitute computational hypotheses requiring mandatory experimental validation. Our findings do not constitute functional epitopes but rather offer a prioritized, evidence-based roadmap for future laboratory investigations. This work significantly accelerates the rational design of HPV therapeutic vaccines by narrowing the focus to the most viable candidates, thereby conserving substantial time and resources in the downstream experimental verification process.

Current treatment protocols for bladder cancer (BC) do not include additional immune checkpoint targets or biomarkers that can accurately predict treatment response. Hence, it is imperative to identify more inclusive and promising candidate compounds for immune checkpoint therapy. Therefore, we sought to investigate whether Fibrinogen Like 1 (FGL1) could serve as a new immune checkpoint for bladder cancer. Cell lines overexpressing/silencing FGL1 in human BC cells (5637, HT1376) were constructed, and the regulatory effects of FGL1 on BC cells proliferation, apoptosis, and the tumor immune microenvironment were detected using experimental techniques such as western blot, immunohistochemistry, immunofluorescence, and flow cytometry in an in vivo/vitro experimental model. Silencing FGL1 inhibited BC cells proliferation, promoted BC cells apoptosis, and stimulated tumor-infiltrating lymphocytes (TILs) activation and expansion in tumor microenvironment (TME) for antitumor immunity. Meanwhile, silencing FGL1 down-regulated the expression level of Lymphocyte Activating 3 (LAG3) to inhibit tumorigenicity in xenograft tumor models. Targeting the FGL1/LAG3 signaling pathway can stimulate bladder cancer TILs activation and expansion for antitumor immunity in TME, which inhibits tumor proliferation and growth and promotes tumor apoptosis. Therefore, FGL1 can be used as a potential immune checkpoint for the treatment of BC.