Cancer Immunology, Immunotherapy最新文献

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking immunotherapy, demonstrating significant efficacy in treating B cell malignancies. In the context of multiple myeloma (MM), B cell maturation antigen (BCMA) has been identified as a critical target, driving the development of CAR T cell therapies designed to address this plasma cell cancer. Various CAR designs, utilizing different BCMA recognition domains, have yielded promising clinical results, leading to the approval of two BCMA-targeting CAR T cell therapies by the US Food and Drug Administration (FDA) for the treatment of MM. This review uniquely examines the BCMA CAR T cell landscape, emphasizing the design of recognition domains, clinical efficacy, and patient outcomes. It critically addresses emerging challenges such as antigen escape and toxicity profiles, which have surfaced alongside therapeutic advances. Moreover, the review spotlights cutting-edge developments, including dual-targeting CAR T strategies, advancements in CAR T cell manufacturing, and innovative allogeneic CAR T approaches utilizing healthy donor cells. By detailing both the breakthroughs and ongoing challenges in BCMA CAR T cell therapy, this review offers a comprehensive perspective on the current state and future possibilities of CAR T cell therapy for MM and its expanding role in treating hematologic malignancies and beyond.

Background: Gastric adenocarcinoma (GAC), particularly the Lauren intestinal-type GAC (IGAC), leads to significant mortality in China due to the limited effectiveness of current treatments. This study aims to investigate the mechanisms of immune suppression in IGAC to identify potential targets for enhancing immunotherapy outcomes.

Methods: Performing an extensive collection and re-analysis of single-cell RNA sequencing (scRNA-seq) of tumor tissues and the corresponding noncancerous mucosae from 15 Chinese patients diagnosed with IGAC, we identified cell subpopulations involved in immune suppression within the tumor microenvironment (TME). We further validated our findings using spatially resolved transcriptomics (SRT), immunofluorescence (IF), and flow cytometry (FCM) on tissues from IGAC patients.

Results: We demonstrated that the TME of IGAC harbors CD8⁺ exhausted T cells (Texs) and various subtypes that mediate immunity. We identified specific subpopulations of Texs (HAVCR2⁺VCAM1⁺) and regulatory T cells (Tregs) (LAYN⁺TNFRSF4⁺) contributing to immune suppression. Furthermore, TNFRSF12A⁺ cancer-associated fibroblasts (CAFs), CTSB⁺ macrophages, and SOD2⁺ monocytes were found to be involved in maintaining the immunosuppressive milieu. SRT and IF assays confirmed the presence and colocalization of these cell types within the tumor tissues, highlighting their functional interactions. FCM assays indicated that the prevalence of HAVCR2⁺VCAM1⁺ Texs and LAYN⁺TNFRSF4⁺ Tregs in tumor tissues was positively associated with IGAC progression.

Conclusions: Detailed profiles of immunosuppressive cell subpopulations in IGAC provide valuable insights into the complexity and heterogeneity of immunosuppression. These findings underscore the necessity for targeted strategies that disrupt specific immunosuppressive pathways, potentially enhancing the efficacy of immunotherapeutic interventions in IGAC.

Tumor-associated macrophages (TAMs) are among the most common types of immune cells in the colon cancer microenvironment. Reprogramming M2-type TAMs with immunosuppressive functions into M1-type TAMs with proinflammatory functions is a novel strategy for reshaping the tumor microenvironment (TME) and enhancing the efficacy of immunotherapy in colon cancer. However, the key molecules and mechanisms underlying TAM polarization require further clarification. Our previous study suggested that ANKRD22 may play a role in regulating the functional state transition of macrophages. However, the expression levels of ANKRD22 in colon TAMs and its specific effects on tumor proliferation remain unclear. In the present study, we observed elevated ANKRD22 expression in M1-type TAMs. The expression level of ANKRD22 was positively correlated with the survival period of patients with colon cancer and with the infiltration abundance of M1-type TAMs, and ANKRD22 expression was negatively correlated with the infiltration abundance of M2-type TAMs. A significant decrease in ANKRD22 expression in macrophages cocultured with colon cancer cell culture supernatant as well as in macrophages directly derived from colorectal cancer tissues was observed. Single-cell RNA sequencing, spatial transcriptomic studies, and subcutaneous xenograft experiments in mice revealed that Ankrd22 silencing altered the subtype distribution of macrophages, attenuated their proinflammatory activity, and enhanced their protumor activity. Additionally, we identified a small-molecule ANKRD22 upregulator that could aid in the development of novel therapeutics targeting TAM remodeling.

Background: Nasopharyngeal carcinoma (NPC), a malignant epithelial tumor, is characterized by a complex tumor microenvironment (TME) and closely associated with metabolic dysfunction. Mitochondrial metabolism plays a crucial role in supporting the rapid proliferation of tumor cells. However, the specific response of mitochondria to the NPC microenvironment and their role in regulating the metabolic heterogeneity of the tumor remain poorly understood.

Methods: Tissue samples and corresponding clinicopathological data were collected from 72 primary NPC patients and 36 non-tumor controls. Histological analysis, coupled with public transcriptomic database interrogation, was utilized to investigate mitochondrial dynamics and metabolism across different cell types. Characterizing the interactions within the tumor-immune microenvironment (TME), we identified mitochondrial genes associated with prognosis in NPC. Additionally, we explored the relationship between key mitochondrial genes, the TME, and the response to immunotherapy.

Results: Malignant epithelial cells in NPC exhibited altered mitochondrial metabolism, including dysregulation of amino acid and glucose metabolism, when compared to non-malignant cells. The mitochondrial-related hub gene KMO was significantly downregulated in NPC tissues relative to normal controls. Low expression of KMO was associated with poorer survival outcomes in patients. Furthermore, KMO expression was negatively correlated with DNA repair mechanisms and hypoxia. In addition, KMO levels were inversely associated with the upregulation of both oxidative phosphorylation (OXPHOS) and glycolysis pathways within the NPC tumor microenvironment (TME). Single-cell transcriptomic analysis revealed that KMO was primarily expressed in B cells, with some contribution from myeloid cells. Importantly, KMO levels positively correlated with the infiltration of various immune cell populations, including B cells, T cells, and macrophages, as well as inflammatory signatures. Further investigation indicated that individuals with elevated KMO expression may exhibit heightened sensitivity to immune checkpoint blockade (ICB) therapy compared to those with lower KMO expression.

Conclusion: The mitochondrial hub gene KMO plays a pivotal role in regulating mitochondrial metabolism and modulating the immune microenvironment in NPC. As a potential prognostic biomarker, KMO may offer valuable predictive insights, and targeting KMO could represent a promising therapeutic strategy for NPC, potentially enhancing the efficacy of immunotherapies.

Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME.

Methods: Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay.

Results: In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C-C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1.

Conclusions: Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC.

Background: CD155 is a crucial factor in the regulation of T cell function and contributes to immune escape. CD155 upregulation has been found in several types of cancer. However, the mechanism by which CD155 regulates CD8⁺ T cell function in colorectal cancer remains unclear. Here we investigated the role and mechanism of CD155 in the regulation of CD8⁺ T cell function.

Methods: We studied the expression of CD155 in colorectal cancer tissues through western blot, immunohistochemistry, and the TCGA database. We verified the effects of CD155 on the functions of colorectal cancer cells and CD8⁺ T cells through in vitro experiments. We demonstrated that CD155 affects CD8⁺ T cell migration and thus promotes tumor growth in a mouse subcutaneous tumor model. We then tested the changes in the PI3K/AKT/NF-κB pathway in CD8⁺ T cells by flow cytometry.

Results: We demonstrated that stable CD155 expression was negatively correlated with prognosis in colorectal cancer patients. In vitro experiments confirmed that CD155 does not affect tumor cell proliferation, migration, or invasion. We also revealed that CD155 downregulated the function and migration of CD8⁺ T cells in vivo and in vitro. Furthermore, CD155 might regulate CD8⁺ T cells function via the PI3K/AKT/NF-κB pathway.

Conclusion: This study revealed that CD155 can promote the progression of colorectal cancer by regulating the PI3K / AKT-NF-κB pathway to promote the depletion of CD8⁺ T cells and reduce their migration to the tumor microenvironment. CD155 may become an important prognostic biomarker and an effective target for colorectal cancer immunotherapy.

Background and aim: Colorectal cancer (CRC) is the third most common cancer globally. Despite advances in curative CRC surgery, metastatic disease remains a significant problem. Emerging evidence suggests that several commonly used perioperative interventions may influence cancer immunity through natural killer (NK) cell function or numbers. This systematic review aimed to identify the effects of standard perioperative interventions on NK cells in CRC patients.

Methods: A systematic search of four databases, MEDLINE, EMBASE, Cochrane Library and Scopus was performed up to 30th July 2024 using keywords associated with colorectal cancer, NK cells and perioperative medications. PRISMA guidelines were followed. Critical appraisal was undertaken using the Joanna Briggs Institute Critical Appraisal tools for quasi-experimental studies and randomised controlled trials.

Results: The literature search identified 10,404 titles and abstracts for screening. Of these, 226 full-text papers were reviewed, and 16 studies were included for data extraction. Results were presented in a narrative synthesis due to study heterogeneity. In vivo studies consistently demonstrated a post-operative decrease in overall cytotoxic capacity and number of NK cells compared to pre-operative levels. This effect was observed across all examined medications, including fentanyl, morphine, propofol and oxycodone. Additionally, blood transfusion also resulted in decreased NK cell cytotoxicity and activity in CRC patients.

Conclusion: While surgical stress is one of the significant factor influencing NK cell cytotoxicity, this review indicates that perioperative intervention also contributes to decreased NK cell cytotoxicity. Our findings demonstrate that certain perioperative interventions (such as ketamine and morphine) can negatively impact NK cell cytotoxicity.

Background: PD-1 blockade plus chemotherapy has become the first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without oncogenic drivers. Oncogenic-driven advanced NSCLC showed limited response to PD-1 blockade monotherapy or chemotherapy alone. Whether NSCLC patients with oncogenic drivers could benefit from PD-1 blockade plus chemotherapy remains undetermined.

Methods: Three hundred twelve NSCLC patients with at least one oncogenic driver alteration received PD-1 plus chemotherapy or each monotherapy were retrospectively identified. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared to evaluate the therapeutic outcomes differences among patients with different oncogenic drivers.

Results: One hundred sixty-two patients received PD-1 blockade plus chemotherapy, 57 received PD-1 blockade monotherapy and 93 received chemotherapy alone were included. Oncogenic driver mutations including KRAS (31.4%), EGFR (28.8%), HER2 (14.7%), BRAF (10.6%), RET (7.4%), and other mutations (7.1%) were identified. Patients with oncogenic drivers who received PD-1 blockade plus chemotherapy had significantly better outcomes compared to those received PD-1 blockade or chemotherapy alone (ORR: 51% vs. 18% vs. 25%, P < 0.001; median PFS: 10.0 [95% CI: 8.9-12.6] vs. 3.7 [95% CI: 2.9-5.1] vs. 5.3 [95% CI: 4.5-6.2] months, P < 0.001; median OS: 26.0 [95% CI: 23.0-30.0] vs. 14.3 [95% CI: 9.6-19.8] vs. 16.1 [95% CI: 11.6-21.9] months, P < 0.001). The superior efficacy was consistently found in separate analyses for patients received first-line and second/third line treatments. Among individual gene alterations, patients with KRAS, EGFR, or BRAF mutations treated with PD-1 blockade plus chemotherapy achieved markedly improved PFS and OS than those received PD-1 blockade or chemotherapy alone. Multivariate Cox regression analysis revealed that PD-1 blockade plus chemotherapy was independently associated with better PFS and OS.

Conclusion: PD-1 blockade plus chemotherapy demonstrated superior efficacy than PD-1 blockade monotherapy or chemotherapy alone in patients with oncogenic-driven advanced NSCLC, particularly in KRAS, EGFR and BRAF subgroups. These findings suggest that PD-1 blockade plus chemotherapy may be considered as an optional treatment option for patients without available targeted therapies.

With the incorporation of immune checkpoint inhibitors into the treatment of endometrial cancer (EC), a deeper understanding of the tumor immune microenvironment is critical. Tertiary lymphoid structures (TLSs) are considered favorable prognostic factors for EC, but the significance of their spatial distribution remains unclear. B cell receptor repertoire analysis performed using six TLS samples located at various distances from the tumor showed that TLSs in distal areas had more shared B cell clones with tumor-infiltrating lymphocytes. To comprehensively investigate the distribution of TLSs, we developed an artificial intelligence model to detect TLSs and determine their spatial locations in whole-slide images. Our model effectively quantified TLSs, and TLSs were detected in 69% of the patients with EC. We identified them as proximal or distal to the tumor margin and demonstrated that patients with distal TLSs (dTLSs) had significantly prolonged overall survival and progression-free survival (PFS) across multiple cohorts [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.36-0.88; p = 0.01 for overall survival; HR, 0.58; 95% CI, 0.40-0.84; p = 0.004 for PFS]. When analyzed by molecular subtype, patients with dTLSs in the copy-number-high EC subtype had significantly longer PFS (HR, 0.51; 95% CI, 0.29-0.91; p = 0.02). Moreover, patients with dTLSs had a higher response rate to immune checkpoint inhibitors (87.5 vs. 41.7%) and a trend toward improved PFS. Our findings indicate that the functions and prognostic implications of TLSs may vary with their locations, and dTLSs may serve as prognostic factors and predictors of treatment efficacy. This may facilitate personalized therapy for patients with EC.

Recent phase 3 randomized controlled trials (RCTs) demonstrate the promising impact of immune checkpoint inhibitor (ICI)-based combination therapies on locally advanced or metastatic urothelial carcinoma (UC). However, comparative data on the efficacy and toxicity of different ICI-based combinations are lacking. This study aims to compare the efficacy of first-line ICI-based combination therapies for locally advanced or metastatic UC using phase 3 RCT data. In November 2023, three databases were searched for RCTs evaluating oncological outcomes in patients with locally advanced or metastatic UC who were treated with first-line ICI-based combination therapies. Network meta-analysis (NMA) was conducted to compare outcomes, including overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), complete response rates (CRRs), and treatment-related adverse events (TRAEs). Subgroup analyses were based on PD-L1 status and cisplatin eligibility. The NMA included five RCTs. Enfortumab vedotin (EV) + pembrolizumab ranked the highest for improving OS (100%), PFS (100%), ORR (96%), and CRR (96%), followed by nivolumab + chemotherapy. EV + pembrolizumab combination superiority held across PD-L1 status and cisplatin eligibility. In patients who are cisplatin-eligible, EV + pembrolizumab significantly improved OS (HR: 0.68, 95%CI 0.47-0.99) and PFS (HR: 0.67, 95%CI 0.49-0.92) compared to nivolumab + chemotherapy. Durvalumab + tremelimumab was the safest combination for severe TRAEs, and EV + pembrolizumab ranked second. Our analyses support EV + pembrolizumab combination as a first-line treatment for locally advanced or metastatic UC. Thus, EV + pembrolizumab may become a guideline-changing standard treatment.