scholarly journals The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors

2020 ◽  
Vol 27 (9) ◽  
pp. R329-R343 ◽  
Author(s):  
Tim J Takkenkamp ◽  
Mathilde Jalving ◽  
Frederik J H Hoogwater ◽  
Annemiek M E Walenkamp
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Neuroendocrine Tumours ◽  
Immune Cell ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Tumour Microenvironment ◽  
Kynurenine Pathway ◽  
Low Grade ◽  
Major Interest

Immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape in numerous types of advanced cancer. However, the majority of patients do not benefit from this treatment modality. Although data are scarce, in general, patients with low-grade neuroendocrine tumours (NETs) do not benefit from treatment with ICIs in contrast to patients with neuroendocrine carcinoma, in which a small subgroup of patients may benefit. Low- and intermediate-grade NETs predominantly lack factors associated with response to ICIs treatment, like immune cell infiltration, and have an immunosuppressive tumour metabolism and microenvironment. In addition, because of its potential influence on the response to ICIs, major interest has been shown in the tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). These enzymes work along the kynurenine pathway that deplete tryptophan in the tumour microenvironment. IDO and TDO are especially of interest in NETs since some tumours produce serotonin but the majority do not, which potentially deplete the precursor tryptophan. In this review, we summarize the current knowledge on the immune tumour microenvironment of neuroendocrine tumours and implications for treatment with immune checkpoint inhibitors. We also discuss (targetable) factors in the NET tumour microenvironment that potentially modulate the anti-cancer immune response.

scholarly journals The Interplay between Inflammation, Anti-Angiogenic Agents, and Immune Checkpoint Inhibitors: Perspectives for Renal Cell Cancer Treatment

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1935 ◽  
Author(s):  
Nicole Brighi ◽  
Alberto Farolfi ◽  
Vincenza Conteduca ◽  
Giorgia Gurioli ◽  
Stefania Gargiulo ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Unmet Need ◽  
Inflammation Markers

Treatment options for metastatic renal cell carcinoma (RCC) have been expanding in the last years, from the consolidation of several anti-angiogenic agents to the approval of immune checkpoint inhibitors (ICIs). The rationale for the use of immunomodulating agents derived from the observation that RCC usually shows a diffuse immune-cell infiltrate. ICIs target Cytotoxic T Lymphocytes Antigen 4 (CTLA-4), programmed death 1 (PD-1), or its ligand (PD-L1), showing promising therapeutic efficacy in RCC. PD-L1 expression is associated with poor prognosis; however, its predictive role remains debated. In fact, ICIs may be a valid option even for PD-L1 negative patients. The establishment of valid predictors of treatment response to available therapeutic options is advocated to identify those patients who could benefit from these agents. Both local and systemic inflammation contribute to tumorigenesis and development of cancer. The interplay of tumor-immune status and of cancer-related systemic inflammation is pivotal for ICI-treatment outcome, but there is an unmet need for a more precise characterization. To date, little is known on the role of inflammation markers on PD-1 blockade in RCC. In this paper, we review the current knowledge on the interplay between inflammation markers, PD-1 axis, and anti-angiogenic agents in RCC, focusing on biological rationale, implications for treatment, and possible future perspectives.

scholarly journals Integrating Circulating Biomarkers in the Immune Checkpoint Inhibitor Treatment in Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3625
Author(s):  
Boris Duchemann ◽  
Jordi Remon ◽  
Marie Naigeon ◽  
Laura Mezquita ◽  
Roberto Ferrara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Circulating Biomarkers ◽  
Liquid Biopsies ◽  
Technical Requirements ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Immune checkpoint inhibitors are now a cornerstone of treatment for non-small cell lung cancer (NSCLC). Tissue-based assays, such as Programmed cell death protein 1 (PD-L1) expression or mismatch repair deficiency/microsatellite instability (MMRD/MSI) status, are approved as treatment drivers in various settings, and represent the main field of research in biomarkers for immunotherapy. Nonetheless, responses have been observed in patients with negative PD-L1 or low tumor mutational burden. Some aspects of biomarker use remain poorly understood and sub-optimal, in particular tumoral heterogeneity, time-evolving sampling, and the ability to detect patients who are unlikely to respond. Moreover, tumor biopsies offer little insight into the host’s immune status. Circulating biomarkers offer an alternative non-invasive solution to address these pitfalls. Here, we summarize current knowledge on circulating biomarkers while using liquid biopsies in patients with lung cancer who receive treatment with immune checkpoint inhibitors, in terms of their potential as being predictive of outcome as well as their role in monitoring ongoing treatment. We address host biomarkers, notably circulating immune cells and soluble systemic immune and inflammatory markers, and also review tumor markers, including blood-based tumor mutational burden, circulating tumor cells, and circulating tumor DNA. Technical requirements are discussed along with the current limitations that are associated with these promising biomarkers.

scholarly journals Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS

2018 ◽  
Vol 2 (17) ◽  
pp. 2242-2252 ◽  
Author(s):  
Takeshi Sugio ◽  
Kohta Miyawaki ◽  
Koji Kato ◽  
Kensuke Sasaki ◽  
Kyohei Yamada ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Therapeutic Options ◽  
Patient Subgroup ◽  
Key Points ◽  
Disease Subtypes

Key Points Microenvironmental immune cell signatures stratify PTCL-NOS patients into clinically meaningful disease subtypes. Immune-checkpoint inhibitors represent potential therapeutic options for a PTCL-NOS patient subgroup.

scholarly journals Combinatorial immunotherapies overcome MYC-driven immune evasion

2021 ◽  
Author(s):  
Joyce V. Lee ◽  
Filomena Houseley ◽  
Christina Yau ◽  
Daniel Van de Mark ◽  
Rachel Nakagawa ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Mhc I ◽  
Number Of Patients ◽  
Tumor Outgrowth

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response. Whether specific oncogenes diminish response to immunotherapy and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed and is associated with worse prognosis, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

scholarly journals Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells

2019 ◽  
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Jun Sasaki ◽  
Chika Kuroda ◽  
Haruka Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Volume ◽  
Tumour Microenvironment ◽  
Osteosarcoma Cell

Abstract Background: There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods: In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. Results: We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions: Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment.

scholarly journals Differences in Immunological Landscape between EGFR-Mutated and Wild-Type Lung Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jia-Wei Luo ◽  
Yan-Hua Guo ◽  
Feng-Ying Wu ◽  
Xue-Fei Li ◽  
Xue-Cheng Sun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Egfr Mutations ◽  
Wild Type ◽  
Egfr Mutant

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients ( P = 0.0065 ). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

scholarly journals Tumour Microenvironment and Immune Evasion in EGFR Addicted NSCLC: Hurdles and Possibilities

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1419 ◽  
Author(s):  
Antonio Santaniello ◽  
Fabiana Napolitano ◽  
Alberto Servetto ◽  
Pietro De Placido ◽  
Nicola Silvestris ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Tumour Microenvironment ◽  
Almost All ◽  
Nsclc Patients

In the last few years, the treatment strategy in Non-Small Cell Lung Cancer (NSCLC) patients has been heavily modified by the introduction of the immune-checkpoint inhibitors. Anti-programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) therapy has improved both progression-free and the overall survival in almost all subgroups of patients, with or without PDL1 expression, with different degrees of responses. However, there are patients that are not benefitting from this treatment. A defined group of immune-checkpoint inhibitors non-responder tumours carry EGFR (epidermal growth factor receptor) mutations: nowadays, anti-PD-1/PD-L1 clinical trials often do not involve this type of patient and the use of immune-checkpoint inhibitors are under evaluation in this setting. Our review aims to elucidate the mechanisms underlying this resistance: we focused on evaluating the role of the tumour microenvironment, including infiltrating cells, cytokines, secreted factors, and angiogenesis, and its interaction with the tumour tissue. Finally, we analysed the possible role of immunotherapy in EGFR mutated tumours.

scholarly journals The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 201 ◽  
Author(s):  
Courèche Kaderbhaï ◽  
Zoé Tharin ◽  
François Ghiringhelli
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Surrogate Marker ◽  
Dna And Rna ◽  
Tumor Mutational Burden ◽  
Tumor Expression

Immune checkpoint inhibitors radically changed the treatment of patients with non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies when used as monotherapy. The assessment of Program Death Ligand-1 (PD-L1) tumor expression by immunohistochemistry is used to select potential responder patients, but this not an optimal marker since it does not predict the absence of anti PD-1 efficacy. Despite this shortcoming, PD-L1 remains the gold standard biomarker in many studies and the only biomarker available for clinicians. In addition to histological markers, transcriptomic and exome analyses have revealed potential biomarkers requiring further confirmation. Recently, tumor mutational burden has emerged as a good surrogate marker of outcome. In this review we will detail current knowledge on DNA and RNA related biomarkers.

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