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

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

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

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1574893616666210707101516 ◽

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.

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SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

10.21203/rs.3.rs-750741/v1 ◽

2021 ◽

Author(s):

Evgeniia Alekseeva ◽

Oksana Stanevich ◽

Maria Sergeeva ◽

Artem Fadeev ◽

Kseniya Komissarova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Neutralizing Antibodies ◽

Immune Escape ◽

Cytotoxic T Cells ◽

Hla Class I ◽

Cd8 T Cell ◽

Hla Class I Antigens ◽

Cell Clones

Abstract Evolution of SARS-CoV-2 in immunocompromised hosts may result in novel variants with changed properties, but the mode of selection underlying this process remains unclear. While escape from humoral immunity certainly plays a role in intra-host evolution, escape from cellular immunity is poorly understood. Here, we report a case of long-term COVID-19 in an immunocompromised patient with non-Hodgkin’s lymphoma who received treatment with rituximab and lacked neutralizing antibodies. Over the 318 days of the disease, the SARS-CoV-2 genome gained a total of 40 changes, 34 of which were present by the end of the study period. Among the acquired mutations, 12 reduced or prevented binding of known immunogenic SARS-CoV-2 HLA class I antigens, suggesting that virus immunoediting is largely driven by cytotoxic CD8 T cell clones. The two changes with the strongest effect, nsp3:T504A and nsp3:T504P, were experimentally assessed in a cytotoxic assay of the patient's CD8 T cells. Both these changes were associated with immune escape, with a stronger effect observed for nsp3:T504P, the change which ultimately got fixed. Together, these results suggest that CD8 T cell escape may be an underappreciated contributor to SARS-CoV-2 evolution in humans.

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Immune escape by Epstein-Barr virus (EBV) carrying Burkitt's lymphoma: in vitro reconstitution of sensitivity to EBV-specific cytotoxic T cells

International Immunology ◽

10.1093/intimm/4.11.1283 ◽

1992 ◽

Vol 4 (11) ◽

pp. 1283-1292 ◽

Cited By ~ 17

Author(s):

M. G. Masucci ◽

Q.-J. Zhang ◽

R. Gavioli ◽

P. O. De Campus–Lime ◽

R. J. Murray ◽

...

Keyword(s):

T Cells ◽

Epstein Barr Virus ◽

Immune Escape ◽

Cytotoxic T Cells ◽

Burkitt’S Lymphoma ◽

Burkitt's Lymphoma ◽

Barr Virus ◽

In Vitro Reconstitution ◽

Epstein Barr

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

International Journal of Molecular Sciences ◽

10.3390/ijms22136741 ◽

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.

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Galectin-3 as a new negative checkpoint of the immune response is the key target for effective immunotherapy against prostate cancer

10.1101/763409 ◽

2019 ◽

Author(s):

Carolina Tiraboschi ◽

Lucas Gentilini ◽

Felipe M. Jaworski ◽

Enrique Corapi ◽

Carla Velazquez ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Immune Escape ◽

Cytotoxic T Cells ◽

Combined Treatment ◽

Clinical Samples ◽

Major Health Problem ◽

Galectin 3 ◽

Prostate Tumor Cells ◽

Immune Escape Mechanisms

AbstractProstate cancer (PCa) is a major health problem worldwide. Taxol derivatives–based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response. However, Docetaxel has been shown to enhance the effectiveness of immunotherapy in a variety of cancers, but to date, the mechanism is still unknown. Herein, we showed first that Galectin-3 (Gal-3) expressed by prostate tumor cells is the principal immunological checkpoint responsible of the failure of immunotherapy; and that Docetaxel leads to the inhibition of Gal-3 expression in PCa cells as well as in clinical samples of mCRPC patients promoting a Th1 response. We thus optimized a prostate cancer animal model that undergoes surgical resection of the tumor like prostatectomy to mimic what is usually performed in patients. More importantly, using low and nontoxic doses of taxane prior to immunotherapy, we were able to directly impact the activation and proliferation of CD8+ cytotoxic T cells through reducing the number of CD8+CD122+CD28-T cells and highly control tumor recurrence. Thus, Gal-3 expression by PCa cells is a key inhibitor for the success of immunotherapy, and low doses of Docetaxel with noncytotoxic effect on leukocyte survival should be used prior to vaccination for all PCa patients. This combined treatment sequence right after surgery would promote the preconditioning of the tumor microenvironment, allowing for effective anti-tumor immunotherapy and can be transferred rapidly to clinical therapeutic protocols.

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