Inhibitory Effect of PD-1/PD-L1 and Blockade Immunotherapy in Leukemia

2021 ◽  
Vol 24 ◽  
Author(s):  
Kai Xing ◽  
Pan Zhou ◽  
Jiaojiao Li ◽  
Miao Liu ◽  
Wei Emma Zhang
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Solid Tumors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Inhibitory Effect ◽  
Main Body ◽  
Intracellular Signals ◽  
Effect Of Pd

Background: PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of a variety of solid tumors. And some clinical trials have also confirmed the excellent efficacy of PD-1/PD-L1 inhibitors on lymphoma. However, the efficacy of PD-1/PD-L1 inhibitors on leukemia remains unclear. Main body: To understand the connection between PD-1/PD-L1 and leukemia better, this review concentrates on the up-regulated expression of PD-1/PD-L1 and the PD-1/PD-L1 blockade trials in participants with leukemia. PD-1/PD-L1 signal performs momentously negative immunoregulation of cancer, which can inhibit the activation of cytotoxic T cells and involve in the immune escape in tumors. Activated PD-1/PD-L1 may transduce negative intracellular signals to block the mitotic cycle and the development of T-cells. Several pathways are involved in these critical biochemical processes, including MAPK, Calcium, PI3K/AKT, and so on. Lately, PD-1/PD-L1 antibodies have illustrated unprecedented curative effects in the field of Hodgkin's lymphoma and some solid tumors. Specimens from patients with leukemia demonstrated the elevated level of PD-1/PD-L1 in T lymphocytes. This finding inspired hematologists to use PD-1/PD-L1 inhibitors for subjects suffering from leukemia. Some clinical trials implied that PD-1/PD-L1 inhibitors could help patients fight against leukemia. However, other researchers reported the opposite results. Conclusions: PD-1/PD-L1 is upregulated in leukemia, but the results regarding PD-1/PD-L1 blockade are mixed and more clinical trials are needed to be conducted.

scholarly journals Double-refractory Hodgkin lymphoma: tackling relapse after brentuximab vedotin and checkpoint inhibitors

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 247-253
Author(s):  
Narendranath Epperla ◽  
Mehdi Hamadani
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cellular Therapy ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Killer Cell ◽  
Brentuximab Vedotin ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract The approval of brentuximab vedotin (BV) and checkpoint inhibitors (CPI) has revolutionized the management of relapsed/refractory classical Hodgkin lymphoma (cHL) patients. In recent years these agents have rapidly moved to earlier lines of therapy, including post-autologous hematopoietic cell transplant (auto-HCT) consolidation, pre-HCT salvage, and the frontline treatment setting. This shift in practice means that double-refractory (refractory to both BV and CPI) cHL is becoming an increasingly common clinical problem. In patients who are not eligible for clinical trials, conventional cytotoxic and targeted therapies (off label) may be a potential option. In patients who are transplant eligible, early referral to allogeneic HCT should be considered given the significant improvement in transplant outcomes in the contemporary era. Cellular therapy options including CD30.chimeric antigen receptor T cells, Epstein-Barr virus-directed cytotoxic T cells, and CD16A/30 bispecific natural killer cell engagers appear promising and are currently in clinical trials.

scholarly journals MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

2021 ◽  
Vol 22 (13) ◽  
pp. 6741
Author(s):  
Elena Shklovskaya ◽  
Helen Rizos
Keyword(s):  
T Cells ◽  
Immune System ◽  
Solid Tumors ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Therapeutic Strategies ◽  
Antigenic Peptides ◽  
Mhc I ◽  
Immune Mediated

It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

Investigating the various predictive values of POLE/POLD1 mutations for response to immune checkpoint inhibitors (ICIs) in different solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2606-2606
Author(s):  
Yanling Niu ◽  
Tonghui Ma ◽  
Yanling Niu ◽  
Tao Li
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Cancer Center ◽  
Cancer Type ◽  
Cancer Dataset ◽  
Predictive Values ◽  
Esophagogastric Cancer ◽  
Cancer Types

2606 Background: Both POLE and POLD1 encode the catalytic subunit of polymerase enzyme complexes involved in DNA replication and repair. The mutations of POLE and POLD1 have been shown to be oncogenic and lead to DNA repair defects and elevated tumor mutation burden (TMB). And patients with POLE/POLD1 mutations are more likely to benefit from ICIs therapy. Previous studies have shown that TMB has divergent predictive value for response to ICIs therapy in different cancer types. We hypothesized that the associations between POLE/POLD1 mutations and ICIs efficacy are also varied in different solid tumors. Therefore, we explored the prediction values of POLE/POLD1 mutations in some cancer types. Methods: The ICIs treatment cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was selected to analyze the association of POLE/POLD1 mutations with ICIs efficacy. TCGA cohort was enrolled for characterizing tumor infiltrating lymphocytes (TILs) with CIBERSORT. The patients were classified into two groups: POLE/POLD1 mutations (Mut) and wildtype (WT). Overall survival (OS) after ICIs therapy was estimated with Kaplan-Meier method. Results: In MSKCC pan-cancer dataset, patients with POLE/ POLD1 mutations had significantly longer median OS after ICIs therapy (34.00 vs 19.00 months, P = 0.0143), indicating that POLE/POLD1 mutations were associated with better immunotherapy outcomes. Then we analyzed the predictive roles in each cancer type. Notably, we found the associations of POLE/POLD1 mutations with longer median OS in NSCLC (Undefined vs 12.00 months, P = 0.05) and esophagogastric cancer (27.00 vs 15.00 months, P = 0.05). However, the associations between POLE/POLD1 mutations and ICIs efficacy were not observed in bladder cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, and colorectal cancer. Furthermore, our data showed that the median TMB was significantly higher in the Mut group for NSCLC (20.2 vs 6.9 muts/Mb, P < 0.0001) and esophagogastric cancer (21.4 vs 5.6 muts/Mb, P < 0.0001). In TCGA esophagogastric cancer cohort, POLE/POLD1 mutations were correlated with decreased naive B cells (P = 0.0306) and increased activated memory CD4+ T cells (P = 0.0224). In TCGA NSCLC cohort, POLE/POLD1 mutations were correlated with elevated gamma delta T cells (P = 0.0219). These data suggested that POLE/POLD1 mutations were also involved in the infiltration of some immune cells. Conclusions: Although POLE/POLD1 mutations were associated with better ICIs efficacy for all the enrolled patients, the prolonged OS was only found in the Mut group for NSCLC and esophagogastric. These data suggested that POLE/POLD1 mutations may be a useful predictor for ICIs efficacy in these two types of cancer. Moreover, POLE/POLD1 mutations were correlated with the level of TILs in NSCLC and esophagogastric. The finding was consistent with the efficacy of immunotherapy.

scholarly journals Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway

Leukemia ◽  
2013 ◽  
Vol 28 (1) ◽  
pp. 236-238 ◽  
Author(s):  
S M Ahmad ◽  
S K Larsen ◽  
I M Svane ◽  
M H Andersen
Keyword(s):  
T Cells ◽  
Immune Escape ◽  
Cytotoxic T Cells

scholarly journals Patterns of TIGIT Expression in Lymphatic Tissue, Inflammation, and Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Niclas C. Blessin ◽  
Ronald Simon ◽  
Martina Kluth ◽  
Kristine Fischer ◽  
Claudia Hube-Magg ◽  
...  
Keyword(s):  
T Cells ◽  
Checkpoint Inhibitors ◽  
Inflammatory Diseases ◽  
Cytotoxic T Cells ◽  
Tissue Microarrays ◽  
Cell Types ◽  
Hashimoto Thyroiditis ◽  
Lung Cancers ◽  
Variable Expression ◽  
Tissue Compartments

TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as >1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 different tumour entities with considerable high variability of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors.

Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors

2017 ◽  
Vol 390 ◽  
pp. 188-200 ◽  
Author(s):  
Shuanglin Han ◽  
Olivier Latchoumanin ◽  
Guang Wu ◽  
Gang Zhou ◽  
Lionel Hebbard ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor

scholarly journals Evolution of immune escape mechanisms in the progression from preinvasive to invasive human lung adenocarcinoma

2020 ◽  
Author(s):  
Nasser K. Altorki ◽  
Alain C. Borczuk ◽  
Vivek Mittal ◽  
Olivier Elemento ◽  
Timothy E. McGraw
Keyword(s):  
T Cells ◽  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Disease Progression ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Treg Cells ◽  
Normal Lung ◽  
Ct Density ◽  
Immune Escape Mechanisms

SummaryThe tumor microenvironment (TME) of lung adenocarcinoma (LUAD) precursor lesions has not been described. We interrogated by multiplex immunofluorescence the TME of preinvasive and invasive Stage 1A LUADs selected by computer tomography (CT) scan-density. Pure non-solid (p-NS) CT density nodules are preinvasive/minimally invasive, whereas solid CT density nodules are frankly invasive cancers. Our data reveal an intensely immune-suppressive immune TME in p-NS tumors characterized by an increase in Treg cells and a decrease in cytotoxic T cells relative to normal lung. The TME of the solid tumor group, more advanced lesions than the p-NS yet still early in disease development, were increasingly more immune-suppressive. Provocatively, there was a further increase in both Treg cells and cytotoxic T cells, establishing a nascent albeit ineffective anti-tumor immune response in transition from preinvasive p-NS to invasive solid tumors. Regulatory T cells play a dominant role throughout progression, while additional immune evasive mechanisms are employed at different stages of disease progression, including T cell exclusion from cancer cell nests early and activation of immune checkpoints later. Our study establishes that different immune-targeted strategies are required to intercept disease progression at these two distinct early points of lung cancer development.Statement of SignificanceUsing multiplexed IF, we compared the cellular composition and activation state of the tumor immune microenvironment between pre/minimally invasive and frankly invasive adenocarcinoma. We found a progressive increase in immunosuppressive mechanisms in association with disease progression suggesting that Interception strategies should be specifically tailored based on underlying immune escape mechanisms

scholarly journals Next-Generation Immunotherapies to Improve Anticancer Immunity

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaoyao Shi ◽  
Katarzyna Tomczak ◽  
June Li ◽  
Joshua K. Ochieng ◽  
Younghee Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Cell Subset ◽  
Cytotoxic T Cell ◽  
Killer Cells

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell–mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.

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