scholarly journals Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade

2022 ◽  
Vol 12 ◽  
Author(s):  
Carlo Genova ◽  
Chiara Dellepiane ◽  
Paolo Carrega ◽  
Sara Sommariva ◽  
Guido Ferlazzo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Regulatory Elements ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Implications ◽  
Investigational Agents

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

scholarly journals The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study

2020 ◽  
Author(s):  
Maria D’Souza ◽  
Dorte Nielsen ◽  
Inge Marie Svane ◽  
Kasper Iversen ◽  
Peter Vibe Rasmussen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Malignant Melanoma ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Absolute Risk ◽  
Cardiovascular Death ◽  
Cardiac Events ◽  
Cox Models ◽  
Hazard Ratios

Abstract Aims The study aimed to estimate the risk of cardiac events in immune checkpoint inhibitor (ICI)-treated patients with lung cancer or malignant melanoma. Methods and results The study included consecutive patients with lung cancer or malignant melanoma in 2011–17 nationwide in Denmark. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, heart failure) or cardiovascular death. Absolute risks were estimated and the association of ICI and cardiac events was analysed in multivariable Cox models. We included 25 573 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7% [95% confidence interval (CI) 6.8–12.5]. Of the 13 568 patients with malignant melanoma, 145 had PD1i and 212 had cytotoxic T-lymphocyte-associated protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks were 6.6% (1.8–11.3) and 7.5% (3.7–11.3). The hazard rates of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from 1st ICI administration, the hazard ratios were 2.14 (95% CI 1.50–3.05) in patients with lung cancer and 4.30 (1.38–13.42) and 4.93 (2.45–9.94) in patients with malignant melanoma with PD1i and CTLA-4i, respectively. After 6 months, HRs were 2.26 (1.27–4.02) for patients with lung cancer and 3.48 (1.91–6.35) for patients with malignant melanoma and CTLA-4i. Conclusions Among patients with lung cancer and malignant melanoma, ICI treated had increased rates of cardiac events. The absolute risks were higher in these data compared with previous pharmacovigilance studies (e.g. 1.8% peri-/myocarditis 1-year risk).

scholarly journals Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 809 ◽  
Author(s):  
Kloten ◽  
Lampignano ◽  
Krahn ◽  
Schlange
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Tissue Samples ◽  
Programmed Death ◽  
Nsclc Patients

Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.

scholarly journals The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Nádia Ghinelli Amôr ◽  
Paulo Sérgio da Silva Santos ◽  
Ana Paula Campanelli
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Molecules

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

scholarly journals Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wenwen Yang ◽  
Caining Lei ◽  
Shaoming Song ◽  
Wutang Jing ◽  
Chuanwei Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Malignant Tumor ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Response ◽  
Inhibitory Molecule

AbstractAfter being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

scholarly journals Dendritic Cell-Based Immunotherapy in Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Dieter Stevens ◽  
Joline Ingels ◽  
Sandra Van Lint ◽  
Bart Vandekerckhove ◽  
Karim Vermaelen
Keyword(s):  
Lung Cancer ◽  
Dendritic Cell ◽  
Immune Checkpoint ◽  
Paradigm Shift ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Responses ◽  
Early Phase Trials

Lung cancer remains the leading cause of cancer-related death worldwide. The advent of immune checkpoint inhibitors has led to a paradigm shift in the treatment of metastatic non-small cell and small cell lung cancer. However, despite prolonged overall survival, only a minority of the patients derive clinical benefit from these treatments suggesting that the full anti-tumoral potential of the immune system is not being harnessed yet. One way to overcome this problem is to combine immune checkpoint blockade with different strategies aimed at inducing or restoring cellular immunity in a tumor-specific, robust, and durable way. Owing to their unique capacity to initiate and regulate T cell responses, dendritic cells have been extensively explored as tools for immunotherapy in many tumors, including lung cancer. In this review, we provide an update on the nearly twenty years of experience with dendritic cell-based immunotherapy in lung cancer. We summarize the main results from the early phase trials and give an overview of the future perspectives within this field.

Engineering nanoparticles to locally activate T cells in the tumor microenvironment

2019 ◽  
Vol 4 (37) ◽  
pp. eaau6584 ◽  
Author(s):  
Dangge Wang ◽  
Tingting Wang ◽  
Haijun Yu ◽  
Bing Feng ◽  
Lei Zhou ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Laser Irradiation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Near Infrared ◽  
Checkpoint Inhibitors ◽  
Immunological Tolerance ◽  
Immune Checkpoint Blockade ◽  
Tumor Resistance ◽  
Nir Laser

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment–activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation–triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.

Potential alteration of tumor microenvironments by β-mercaptoethanol

2020 ◽  
Author(s):  
Robert E Click
Keyword(s):  
Molecular Weight ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Suppressor Cells ◽  
Low Molecular Weight ◽  
Uptake Inhibition ◽  
Tumor Microenvironments

The therapeutic effectiveness of immune checkpoint inhibitors in cancer patients is quite profound. However, it is generally accepted that further progress is curtailed by accompanying adverse events and by low cure rates linked to the tumor microenvironment. The multitudes of immune processes altered by low-molecular-weight thiols published over the past decades suggest they have potential to alter tumor microenvironment processes which could result in an increase in immune checkpoint inhibitor survival rates. Based on one of the most studied and most potent low-molecular-weight thiols, β-mercaptoethanol (BME), it is proposed that clinical assessment be undertaken to identify any BME benefits with relevance for proliferation/differentiation of immune cells, lymphocyte exhaustion, immunogenicity of tumor antigens and inactivation of suppressor cells/factors. The BME alterations projected to be most effective are: maintenance/replacement of glutathione in lymphocytes via facilitation of cysteine uptake, inhibition of suppressor cells/soluble factors and inactivation of free-radical, reactive oxygen species.

EXTRATUMOR MICROENVIRONMENT IN RENAL CELL CARCINOMA

2021 ◽  
Vol 2 (4) ◽  
pp. 5-12
Author(s):  
Mirzagaleb Tillyashaykhov ◽  
◽  
Elena Boyko ◽  
Shakhnoza Jumaniyazova
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Animal Tumor

The review is focused on studying the immunosuppressive mechanisms acting in the microenvironment of renal cell carcinoma tumors. The report contains a collection of basic literature materials on the study of tumor growth factors that boost tumor cell proliferation and metastasis. The tumor microenvironment (TME) limits the immune surveillance of tumor-associated antigens and the effectiveness of immune checkpoint inhibitors. Although renal cell carcinoma is one of several tumor types sensitive to immune checkpoint inhibitors, the efficacy of these agents is likely to be limited by different tumor-infiltrating myeloid cells of bone marrow that make up the TME. Several strategies aimed at eliminating the onset of these cells in tumor tissue or neutralizing their immunosuppressive function have shown encouraging results in animal tumor models and clinical trials.Keywords: cytotoxic T lymphocytes (CTL), immune checkpoint inhibitor (ICI), tumor microenvironment (MEV), myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), renal cell carcinoma (RCC), tumor-associated macrophages (TAM), vascular endothelial growth factor (VEGF)

scholarly journals Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yalei Zhang ◽  
Ye Li ◽  
Kun Chen ◽  
Ling Qian ◽  
Peng Wang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Tumor Resistance ◽  
Systemic Delivery ◽  
Future Directions ◽  
Immunosuppressive Tumor Microenvironment ◽  
Proinflammatory Factors

AbstractIt has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.

scholarly journals The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 140 ◽  
Author(s):  
Koichi Saruwatari ◽  
Ryo Sato ◽  
Shunya Nakane ◽  
Shinya Sakata ◽  
Koutaro Takamatsu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Lung Squamous Cell Carcinoma ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
Advanced Cancer Patients

Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular disease and is closely associated with being positive for anti-acetylcholine receptor (anti-AChR) Abs, which are high specific and diagnostic Abs for MG. Methods: A 72-year-old man was diagnosed with chemotherapy-refractory lung squamous cell carcinoma and nivolumab was selected as the third-line regimen. We describe the first report of an anti-AChR Ab-seropositive lung cancer patient achieving a durable complete response (CR) to an anti-PD-1 antibody therapy. To further explore this case, we performed multiplex immunofluorescence analysis on a pretreatment tumor. Results: The patient achieved a durable CR without developing MG. However, the levels of anti-AChR Abs were elevated during two years of anti-PD-1 antibody therapy. The tumor of the subclinical MG patient had high PD-L1 expression and an infiltrated–inflamed tumor immune microenvironment. Conclusions: This study suggests that immune checkpoint inhibitors can be safely used and provide the benefits for advanced cancer patients with immunologically ‘hot’ tumor even if anti-AChR Abs are positive. Although careful monitoring clinical manifestation in consultation with neurologist is needed, immune checkpoint inhibitors should be considered as a treatment option for asymptomatic anti-AChR Ab-seropositive cancer patients.

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