Revealing the therapeutic properties of gut microbiota: transforming cancer immunotherapy from basic to clinical approaches.

The immune system plays a pivotal role in the battle against cancer, serving as a formidable guardian in the ongoing fight against malignant cells. To combat these malignant cells, immunotherapy has emerged as a prevalent approach leveraging antibodies and peptides such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 to inhibit immune checkpoints and activate T lymphocytes. The optimization of gut microbiota plays a significant role in modulating the defense system in the body. This study explores the potential of certain gut-resident bacteria to amplify the impact of immunotherapy. Contemporary antibiotic treatments, which can impair gut flora, may diminish the efficacy of immune checkpoint blockers. Conversely, probiotics or fecal microbiota transplantation can help re-establish intestinal microflora equilibrium. Additionally, the gut microbiome has been implicated in various strategies to counteract immune resistance, thereby enhancing the success of cancer immunotherapy. This paper also acknowledges cutting-edge technologies such as nanotechnology, CAR-T therapy, ACT therapy, and oncolytic viruses in modulating gut microbiota. Thus, an exhaustive review of literature was performed to uncover the elusive link that could potentiate the gut microbiome's role in augmenting the success of cancer immunotherapy.

A systematic review and meta-analysis of observational studies and uncontrolled trials reporting on the use of checkpoint blockers in patients with cancer and pre-existing autoimmune disease.

BACKGROUND: Cancer patients with autoimmune disease have been excluded from randomized trials of immune checkpoint blockers (ICBs). We conducted a systematic review of observational studies and uncontrolled trials including cancer patients with pre-existing autoimmune disease who received ICBs. METHODS: We searched 5 electronic databases through November 2023. Study selection, data collection, and quality assessment were performed independently by 2 investigators. We performed a meta-analysis to pool incidence of immune-related adverse events (irAEs), including de novo events and flares of existing autoimmune disease, hospitalizations due to irAEs, as well as deaths. RESULTS: A total of 95 studies were included (23,897 patients with cancer and preexisting autoimmune disease). The most common cancer evaluated was lung cancer (30.7 %) followed by skin cancer (15.7 %). Patients with autoimmune disease were more likely to report irAEs compared to patients without autoimmune disease (relative risk 1.3, 95 % CI 1.0 to 1.6). The pooled occurrence rate of any irAEs (flares or de novo) was 61 % (95 % CI 54 % to 68 %); that of flares was 36 % (95 % CI 30 % to 43 %), and that of de novo irAEs was 23 % (95 % CI 16 % to 30 %). Flares were mild (grade <3) in half of cases and more commonly reported in patients with psoriasis/psoriatic arthritis (39 %), inflammatory bowel disease (37 %), and rheumatoid arthritis (36 %). 32 % of the patients with irAEs required hospitalization and treatment of irAEs included corticosteroids in 72 % of the cases. The irAEs mortality rate was 0.07 %. There were no statistically significant differences in cancer response to ICBs between patients with and without autoimmune disease. CONCLUSIONS: Although more patients with pre-existing autoimmune disease had irAEs, these were mild and managed with corticosteroids in most cases, with no impact on cancer response. These results suggest that ICBs can be used in these patients, but careful monitoring is required, as over a third of the patients will experience a flare of their autoimmune disease and/or require hospitalization. These findings provide a crucial foundation for oncologists to refine their monitoring and management strategies, ensuring that the benefits of ICB therapy are maximized while minimizing its risks.

Acute aortic catastrophe caused by cardiovascular oncological manipulation by tyrosine kinase inhibitors with immune checkpoint blockades: a case report and literature review.

Background: Tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) inhibitor pathway with immune checkpoint blockade have shown promising outcomes in managing metastatic renal cancer. However, they increase the risk of a person developing high blood pressure and cardiovascular complications. Case summary: In this study, we report the case of a 73-year-old woman on axitinib and pembrolizumab for her Stage 4 renal cell carcinoma. She presented with intractable chest pain and high systolic blood pressure, not responding to opiates. Her computed tomography angiography results showed an acute intra-mural haematoma with a rupture in the descending thoracic aorta. She underwent emergency thoracic endovascular aortic repair. Post-operatively, she recovered fully without any neurological or cardiovascular issues. Discussion: The severity of cardiovascular haemodynamic complications arising from the consumption of VEGF inhibitors and from immunotherapy and the lack of anti-hypertensive strategies to adequately manage such events require an unequivocal and urgent assessment of their cardiovascular safety. This case highlights the crucial role of cardiovascular oncology in managing such acute aortic catastrophes.

Cyclin-dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple-negative breast cancer by affecting the immune microenvironment.

BACKGROUND: Clinical studies on programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors for treating triple-negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor-infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin-dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies. METHODS: The authors tested three CDK inhibitors on the TNBC cell lines MDA-MB-231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune-related mechanisms of different combination therapy experiments in a 4T1 cell-transplanted BALB/c mouse model. RESULTS: Treatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell-cycle arrest and induced apoptosis in human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD-L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels. CONCLUSIONS: Combination therapy with CDK and PD-L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

Prognostic implication of UBE2C + CD8 + T cell in neoadjuvant immune checkpoint blockade plus chemotherapy for locally advanced esophageal cancer.

BACKGROUND: Immune checkpoint blockers (ICBs) plus chemotherapy as neoadjuvant therapy for patients with esophageal cancer (EC) has gained substantial attention. This study aimed to investigate the early and mid-term outcome of neoadjuvant ICBs plus chemotherapy and discover immune-associated predictors of major pathological response (MPR) for locally advanced EC. METHOD: Patients with locally advanced EC who received neoadjuvant ICBs plus chemotherapy were retrospectively included between June 2019 to December 2021. Conjoint analysis of Bulk-RNA seq (GSE165252) and scRNA seq (GSE188900) were used to investigate potential prognostic factors and immunological mechanisms, then multiplexed immunofluorescence was applied to validate. RESULTS: 76 patients were included. A total of 21 (27.6 %) patients achieved MPR, with 13 (17.1 %) attaining a pathological complete response. Over a median follow-up of 1.8 years, 6 (7.9 %) patients died and 21 (27.6 %) experienced disease recurrence within 0.6 to 2.1 years after surgery. The overall survival rate and recurrence-free survival rate were 93.3 + 2.9 % and 84.8 + 4.2 % at 12 months, 90.8 + 3.7 % and 67.1 + 6.4 % at 24 months, and 90.8 + 3.7 % and 62.9 + 7.2 % at 36 months, respectively. Patients achieving MPR had a significantly lower risk of recurrence compared to non-responders (9.5 % vs 34.5 %, P = 0.017). Analysis of bulk-RNA seq and scRNA-seq revealed that UBE2C and UBE2C + CD8 + T cells were adverse prognostic factors. Immunohistochemistry demonstrated that the non-MPR group had a higher infiltration of UBE2C + immune cells than MPR group after neoadjuvant treatment. Multiplexed immunofluorescence confirmed that infiltrating UBE2C + CD8 + T cells in MPR group were significantly fewer than non-MPR group after neoadjuvant treatment, indicating their poor prognostic role for EC. CONCLUSIONS: Neoadjuvant ICBs plus chemotherapy shows promising efficacy in locally advanced EC, with MPR being a significant predictor of lower recurrence risk. Immunological analyses identified UBE2C + CD8 + T cells as adverse prognostic factors, suggesting their potential as biomarkers for patient stratification and treatment response.

Emerging therapeutic approaches of SHP2-targeted modulators.

Tweetable abstract Monotherapy and combination therapy of SHP2 regulator for cancer treatment.

Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells.

Current immunotherapies provide limited benefits against T cell-depleted tumors, calling for therapeutic innovation. Using multi-omics integration of cancer patient data, we predict a type I interferon (IFN) responseHIGH state of dendritic cell (DC) vaccines, with efficacious clinical impact. However, preclinical DC vaccines recapitulating this state by combining immunogenic cancer cell death with induction of type I IFN responses fail to regress mouse tumors lacking T cell infiltrates. Here, in lymph nodes (LNs), instead of activating CD4+/CD8+ T cells, DCs stimulate immunosuppressive programmed death-ligand 1-positive (PD-L1+) LN-associated macrophages (LAMs). Moreover, DC vaccines also stimulate PD-L1+ tumor-associated macrophages (TAMs). This creates two anatomically distinct niches of PD-L1+ macrophages that suppress CD8+ T cells. Accordingly, a combination of PD-L1 blockade with DC vaccines achieves significant tumor regression by depleting PD-L1+ macrophages, suppressing myeloid inflammation, and de-inhibiting effector/stem-like memory T cells. Importantly, clinical DC vaccines also potentiate T cell-suppressive PD-L1+ TAMs in glioblastoma patients. We propose that a multimodal immunotherapy and vaccination regimen is mandatory to overcome T cell-depleted tumors.

Monophosphoryl lipid A-assembled nanovaccines enhance tumor immunotherapy.

Therapeutic cancer nanovaccines can induce strong antitumor immunity and establish long-term immune memory and have shown potential for curing tumors in some clinical trials. However, weak immunogenicity and safety concerns of nanocarriers limit the clinical translation of some therapeutic nanovaccines. Here, we developed minimal-component cancer nanovaccines, monophosphoryl lipid A (MPLA)-assembled nanovaccines (MANs), that could facilitate the clinical application of nanovaccines. The MANs were formed by protein antigens extracted from chemotherapy-induced tumor cell cultures and the amphiphilic immune adjuvant MPLA. Compared with free chemotherapy-induced antigens, MANs can activate the Toll-like receptor 4 (TLR4)-mediated signalling pathway and promote adaptive immunity against tumor antigens. Mechanistic analysis indicated that MANs induced antigen capture of DCs and promoted the activation of DCs and T cells, thereby optimizing the ratio of CD8+ T/Tregs in tumors and facilitating the transformation of the tumor immune microenvironment (TIME) from "cold" to "hot". In a CT26 colorectal cancer model, MANs+αPD-1 significantly improved the efficacy of αPD-1 treatment. Our work offers a strategy for designing minimal-component cancer nanovaccines with potential clinical benefits. STATEMENT OF SIGNIFICANCE: To address the weak immunogenicity of cancer vaccines and the safety concerns of nanocarriers, we prepared MPLA-assembled nanovaccines (MANs) using chemotherapy induced antigens and the immune adjuvant MPLA to promote cancer vaccines to clinical practice. MANs effectively internalized tumor antigens and induced DC maturation, indicating that the initial anti-tumor response had been activated. MANs+αPD-1 induced APCs, CD8+ T cells and memory T cells with positive anti-tumor effects to migrate to tumor tissue, thus leading to the transformation of the tumor immune microenvironment from "cold" to "hot". At the animal level, the combination of MANs and αPD-1 exerted synergistic effects and significantly enhanced tumor immunotherapy. Therefore, the treatment regimen of MANs+αPD-1 has potential clinical benefits.

Evaluation safety and efficacy of immune checkpoint blockers (ICB) and radiotherapy combination versus ICB in non-small cell lung cancer patients with recurrence or metastasis: A systematic review and meta-analysis.

BACKGROUND: Currently, immune checkpoint blockers (ICB) and radiotherapy (RT) combination therapy is broadly applied in non-small cell lung cancer (NSCLC) patients. However, meta-analysis about safety and efficacy of RT + ICB versus ICB has not yet been reported. To evaluate safety and efficacy of the combination therapy of ICB and RT in patients with recurrent or metastatic NSCLC and explore factors related to higher response rates, longer lifetime, and lower toxicity, meta-analysis of previous clinical data will be presented in this article. METHODS: A literature search on patients with recurrent or metastatic NSCLC treated with RT + ICB versus ICB was performed using the Cochrane Library, Embase and PubMed up to December 10, 2022. Suitable quality assessment checklists were selected corresponding to various types of research studies. Comparative and single-arm studies were analyzed using Stata 14.0. RESULTS: 10 comparative studies and 15 arms of combination therapy were included for this meta-analysis. RT significantly improved objective response rate (ORR), disease control rate (DCR), and overall survival (OS) and progression-free survival (PFS) of ICB (I-square value (I2 ) = 0.00%, odds ratio (OR) 1.28, 95% confidence interval (CI) 1.09-1.49, I2 = 0.00%, OR 1.12, 95% CI 1.00-1.25, I2 = 42.1%, OR 0.81, 95% CI 0.72-0.92, I2 = 34.5%, OR 0.80, and 95% CI 0.71-0.89, respectively). Toxicity between combination therapy and ICB monotherapy did not significantly differ in any grade or in ≥3 grade of tr-AEs (I2 = 0.00%, OR 1.05, 95% CI 0.91-1.22, I2 = 0.00%, OR 1.46, 95% CI 0.90-2.37, respectively). Subgroup analyses based on single-arm studies showed that applications of SRS/SBRT, PD-1 inhibitor, and administration of ICB after RT were conducive to a better DCR, longer OS and mild adverse events (heterogeneity between groups (HBG) all p < 0.05). CONCLUSION: RT can significantly improve ORR, DCR, OS, and PFS of ICB in patients with recurrent or metastatic NSCLC without increasing toxicity. PD-1 inhibitor following SRS/SBRT could be the best option to maximally benefit the patients.

Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer.

Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)-a herbal compound-and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.

Trial watch: chemotherapy-induced immunogenic cell death in oncology.

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.

Identification of the most effective subgroup of advanced hepatocellular carcinoma from immune checkpoint blocker treatment: a meta-analysis.

Aims: This work was designed to identify the subgroup of advanced hepatocellular carcinoma (HCC) patients for whom treatments containing immune checkpoint blockers (ICBs) were most effective. Materials & methods: A meta-analysis was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs. Results: A total of 2228 patients from four randomized control trials were included. Treatments containing ICBs had better overall survival, progression-free survival and higher objective response rate over treatment without ICBs. Subgroup analysis revealed that treatments containing ICBs were highly effective in improving the overall survival of males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients. Conclusion: Treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Immune checkpoint blockers (ICBs) have significantly improved the prognosis of advanced cancers. However, some patients still cannot benefit from ICBs. The use of ICBs in the treatment of advanced hepatocellular carcinoma (HCC) started late. The subgroup of advanced HCC patients that will benefit most from treatments containing ICBs is still largely unknown. Therefore, a meta-analysis (meta-analysis is a statistical method used to compare or synthesize research results on the same scientific problem) was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs (ICBs alone or in combination with anti-VEGF agents). The results show that treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Cutaneous Adverse Reactions of Immunotherapy in Patients with Advanced Melanoma.

Immune checkpoint blockers (ICBs) have been widely used during the last decade for the treatment of various tumors, including advanced and metastatic melanoma. While these agents have improved melanoma patients' survival rates, they have also been associated with various autoimmune toxicities, with the skin being most commonly affected. The severity of cutaneous toxicity can not only negatively affect patients' quality of life but can also limit the proper treatment of cancer. Thus, the role of the dermatologist is substantial in early detecting and promptly treating these adverse events. Maculopapular rash, psoriasiform, lichenoid dermatoses and bullous pemphigoid are the most frequent cutaneous adverse events that require immediate intervention. Other rare autoimmune toxicities, e.g., sarcoidosis, dermatomyositis or subacute lupus, have also been reported. In this review, we summarize the aspects of ICB-induced cutaneous toxicities in patients with melanoma, emphasizing their management and treatment options in clinical practice.

Construction of a prognostic model for HCC based on ferroptosis-related lncRNAs expression and its potential to predict the response and irAEs of immunotherapy.

Background: Ferroptosis is an iron-dependent programmed cell death process, and studies have confirmed that it plays an important regulatory role in the occurrence and development of various malignancies including hepatocellular carcinoma (HCC). In addition, the role of abnormally expressed long non-coding RNAs (lncRNAs) in regulating and driving the occurrence and development of HCC has attracted more and more attention. However, there is still a lack of research on the role of ferroptosis-related lncRNAs in the prognosis prediction of HCC patients. Method: In this study, we used the Pearson test method to analyze the association between differentially expressed lncRNAs and ferroptosis-related genes in HCC and normal tissues obtained from The Cancer Genome Atlas (TCGA), and found 68 aberrantly expressed and prognosis-related ferroptosis-related lncRNAs. Based on this, we established an HCC prognostic model composed of 12 ferroptosis-related lncRNAs. In addition, HCC patients were divided into a high-risk group and a low-risk group according to the risk score of this 12 ferroptosis-related lncRNAs prognostic model. Gene enrichment analysis indicated that ferroptosis-related lncRNA-based expression signatures may regulate HCC immune microenvironment signaling pathways through ferroptosis, chemical carcinogenesis-reactive oxygen species, and NK cell-mediated cytotoxicity pathways. In addition, immune cell correlation analysis showed that there were significant differences in immune infiltrating cell subtypes, such as Th cells, macrophages, monocytes, and Treg cells between the two groups. In addition, the expression of multiple immune checkpoint molecules was found to be significantly increased in the high-risk group (eg, PD1, CTLA-4, CD86, etc.). Results: Our research provides a new method for predicting prognosis using a ferroptosis-related lncRNA expression signature prognostic model in hepatocellular carcinoma. And it provides new tools for predicting patient response and adverse effects of immunotherapy. Conclusion: In conclusion, ferroptosis-related lncRNA expression signatures can be used to construct a prognostic prediction model to predict the overall survival of HCC patients, and can be used as an independent influencing factor for prognosis. Further analysis showed that ferroptosis-related lncRNAs may affect the efficacy of immunotherapy in patients with HCC by altering the tumor microenvironment, so this model may serve as a new indicator of the response and irAEs of HCC to immunotherapy.

Trial watch: Toll-like receptor ligands in cancer therapy.

Accumulating evidence indicates that Toll-like receptor (TLR) agonists proficiently (re)instore cancer immunosurveillance as immunological adjuvants. So far, three TLR agonists have been approved by regulatory agencies for use in oncological applications. Additionally, these immunotherapeutics have been extensively investigated over the past few years. Multiple clinical trials are currently evaluating the combination of TLR agonists with chemotherapy, radiotherapy, or different immunotherapies. Moreover, antibodies targeting tumor-enriched surface proteins that have been conjugated to TLR agonists are being developed to stimulate anticancer immune responses specifically within the tumor microenvironment. Solid preclinical and translational results support the favorable immune-activating effects of TLR agonists. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for anticancer immunotherapy.

Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood-tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a "hot" tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.

Immune checkpoint blockers in patients with unresectable or metastatic thymic epithelial tumours: A meta-analysis.

BACKGROUND: For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice. METHODS: We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy. RESULTS: Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3-26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6-34.6) and 66.9% (95% CI: 59.6-75.2%), respectively. The incidence of grade 3-5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma. CONCLUSIONS: Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.

HiJAKing Immunotherapy-Resistant Melanoma for a Cure.

Immune checkpoint blockers (ICBs) have brought great promise to patients with advanced melanoma, a tumor type that was claimed largely incurable not long ago. However, therapeutic resistance to ICBs has limited their utility in the clinic. Here, we provide a commentary on recent research endeavors concerning ICB resistance in melanoma patients.

Tim3scFv-Transforming Lactobacillus Inhibits Transplanted Tumor of Renal-Cell Carcinoma.

INTRODUCTION: T-cell immunoglobulin-3 (Tim-3) antibody drugs can treat malignant renal tumors but are expensive. To overcome this limitation, Lactococcus lactis host bacteria were used to express Tim-3 single-chain antibodies. METHODS: The pLAN-CTB-Tim3scFv plasmid was constructed using molecular cloning technology and transformed into Lactococcus lactis. Expression and immune activity of proteins in the transformed bacteria were analyzed using Western blotting and enzyme-linked immunosorbent assay in vitro. A mouse subcutaneously transplanted tumor model of renal adenocarcinoma was constructed. The promoting effect of transformed bacteria on mouse spleen lymphocyte activation and their inhibitory effect on transplanted tumors were analyzed. RESULTS: Transformed L. lactis NZ-CTB-Tim3scFv and NZ-Tim3scFv were successfully constructed. CTB-Tim3scFv secreted by NZ-CTB-Tim3scFv showed immunological activity. Compared with the NZ-Tim3scFv and NZ-Vector groups, the subgroups of splenic lymphocytes in the NZ-CTB-Tim3scFv group had a higher proportion of CD3+CD4+, CD3+CD8a+, and CD3+CD69+ cells. Ki67 and CD31 expression in the NZ-CTB-Tim3scFv group was significantly reduced. Tumor volume in the NZ-CTB-Tim3scFv group increased the least. DISCUSSION/CONCLUSION: Secretion of CTB-Tim3scFv promoted the proliferation and activation of spleen lymphocytes and inhibited growth, cell proliferation, and angiogenesis of tumors. The proposed method is low cost and convenient with potential to become a new immunotherapy approach for renal-cell carcinoma.