The application and mechanism of PD pathway blockade for cancer therapy

Research in cancer therapeutics has achieved major progress in the understanding of the tumour-immunity cycle, which controls the delicate balance between the immune system and tumour. Identification of cancer cell T-cell inhibitory signals, including PD-L1, has generated novel insight into how to reinvigorate the patients’ immune cells to respond to a variety of tumour types. PD-1 and PD-L1 (PD) inhibitory pathway blockade appears to a highly promising therapy and could accomplish durable anti-tumour responses with a reasonable toxicity profile. Some of the FDA-approved mAbs can reverse the negative regulators from tumour cells and antigen presenting cells of T-cell function to treat some cancer types by blocking the PD signalling pathway,especially advanced solid tumours. Emerging clinical data suggest that cancer immunotherapy will become a significant part of the clinical treatment of cancer.

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CERI, CEFX, and CPI: Largely Improved Positive Controls for Testing Antigen-Specific T Cell Function in PBMC Compared to CEF

Cells ◽

10.3390/cells10020248 ◽

2021 ◽

Vol 10 (2) ◽

pp. 248

Author(s):

Alexander A. Lehmann ◽

Pedro A. Reche ◽

Ting Zhang ◽

Maneewan Suwansaard ◽

Paul V. Lehmann

Keyword(s):

T Cell ◽

Mononuclear Cells ◽

Cell Function ◽

Racial Bias ◽

Immune Monitoring ◽

Functional Fitness ◽

Peripheral Blood Mononuclear ◽

Cell Immunity ◽

Antigen Presenting ◽

Positive Controls

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of peripheral blood mononuclear cells (PBMCs) before the actual test is performed can introduce numerous variables that may jeopardize the results. Therefore, no T cell test is valid without assessing the functional fitness of the PBMC being utilized. This can only be accomplished through the inclusion of positive controls that actually evaluate the performance of the antigen-specific T cell and antigen presenting cell (APC) compartments. For Caucasians, CEF peptides have been commonly used to this extent. Moreover, CEF peptides only measure CD8 cell functionality. We introduce here universal CD8+ T cell positive controls without any racial bias, as well as positive controls for the CD4+ T cell and APC compartments. In summary, we offer new tools and strategies for the assessment of PBMC functional fitness required for reliable T cell immune monitoring.

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Cancer Immunology

DeckerMed Surgery ◽

10.2310/surg.2209 ◽

2015 ◽

Author(s):

Clifford S. Cho ◽

Amanda Contreras

Keyword(s):

Immune System ◽

T Cell ◽

Cell Function ◽

Cytotoxic T Lymphocyte ◽

Continuous Process ◽

Effective Means ◽

Full Complement ◽

Activated T Cell ◽

Antigen Presenting ◽

Cell Inhibition

The immune system conducts a continuous process of immunologic surveillance for new cancer cells that is likely capable of eradicating many potential malignancies before they become clinically evident. Nascent tumors can, however, use escape mechanisms to avoid this control. It is hoped that therapeutic manipulation of this balance between cancer and host may allow us to harness the immune system as an effective means of treating established tumors. This review summarizes the immunologic response, immunoediting, and clinical strategies in cancer immunotherapy. Figures show activation of CD8+ cytotoxic T lymphocytes and CD4+ T helper cells by an antigen-presenting cell; inhibition of T cells specific for an antigen being presented in the absence of a full complement of costimulatory interactions, as might be present on an immature dendritic cell, engagement of cytotoxic T lymphocyte–associated protein 4 by B7, which serves to downregulate T cell function, and downregulation of major histocompatibility proteins on the surfaces of tumor cells; and the kinetics of activated T cell homeostasis in the presence of cancer. This review contains 3 figures and 39 references.

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Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo

Nature Medicine ◽

10.1038/nm962 ◽

2003 ◽

Vol 9 (12) ◽

pp. 1469-1476 ◽

Cited By ~ 210

Author(s):

Douglas G Millar ◽

Kristine M Garza ◽

Bernhard Odermatt ◽

Alisha R Elford ◽

Nobuyuki Ono ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Antigen Presenting Cell ◽

Antigen Presenting

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Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice

Diabetes ◽

10.2337/db05-0810 ◽

2006 ◽

Vol 55 (7) ◽

pp. 2098-2105 ◽

Cited By ~ 50

Author(s):

P. Alard ◽

J. N. Manirarora ◽

S. A. Parnell ◽

J. L. Hudkins ◽

S. L. Clark ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cell Function ◽

Nod Mice ◽

Antigen Presenting Cell ◽

Diabetes Development ◽

Antigen Presenting

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Dysregulated luminal bacterial antigen-specific T-cell responses and antigen-presenting cell function in HLA-B27 transgenic rats with chronic colitis

Immunology ◽

10.1111/j.1365-2567.2005.02206.x ◽

2005 ◽

Vol 116 (1) ◽

pp. 112-121 ◽

Cited By ~ 16

Author(s):

Bi-Feng Qian ◽

Susan L. Tonkonogy ◽

Frank Hoentjen ◽

Levinus A. Dieleman ◽

R. Balfour Sartor

Keyword(s):

T Cell ◽

Cell Function ◽

T Cell Responses ◽

Bacterial Antigen ◽

Hla B27 ◽

Chronic Colitis ◽

Transgenic Rats ◽

Antigen Presenting Cell ◽

Cell Responses ◽

Antigen Presenting

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The B7/BB1 antigen is expressed by Reed-Sternberg cells of Hodgkin's disease and contributes to the stimulating capacity of Hodgkin's disease-derived cell lines

Blood ◽

10.1182/blood.v82.9.2845.bloodjournal8292845 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2845-2852 ◽

Cited By ~ 1

Author(s):

J Delabie ◽

JL Ceuppens ◽

P Vandenberghe ◽

M de Boer ◽

L Coorevits ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hodgkin's Disease ◽

Cell Function ◽

Cell Lymphoma ◽

Hodgkin’S Disease ◽

B Cell Lymphoma ◽

Accessory Cell ◽

Hodgkin's Lymphomas ◽

Antigen Presenting

The B7/BB1 molecule has recently been found to be expressed on professional antigen-presenting cells and to be the natural ligand for CD28 and CTLA-4 on T cells. On binding of B7/BB1, CD28 transduces a signal that synergizes with triggering of the T-cell antigen receptor, resulting in enhanced cytokine secretion. In view of the data supporting an antigen-presenting function of Reed-Sternberg cells, we evaluated the expression of B7/BB1 in lymph nodes affected by Hodgkin's disease. B7/BB1 was found to be strongly expressed by the Reed- Sternberg cells in all 47 cases of Hodgkin's disease studied. Moreover, Reed-Sternberg cells were frequently surrounded by CD28-expressing T cells. Evidence for a functional role of B7/BB1 on Reed-Sternberg cells was obtained by our findings that T-cell proliferation and interleukin- 2 (IL-2) production in the primary allogenic mixed lymphocyte reaction (MLR), using the B7/BB1-expressing Hodgkin's disease-derived cell lines L428 and KM-H2 as stimulators, could be partially blocked by adding anti-B7 monoclonal antibody. B7/BB1 expression was also evaluated in a group of non-Hodgkin's lymphomas (n = 46). Whereas B7/BB1 was not expressed by the neoplastic cells of most non-Hodgkin's lymphomas, including T-cell-rich B-cell lymphoma (n = 11), it was present on the neoplastic cells of anaplastic large-cell lymphoma (Ki-1 lymphoma) (n = 5) and follicular lymphoma (n = 4). Our data provide further evidence for an accessory cell function of Reed-Sternberg cells. The accessory cell function of Reed-Sternberg cells might lead to pronounced T-cell activation in vivo, which might contribute to the Hodgkin's syndrome. In addition, our study indicates that B7/BB1 may be a useful marker for differentiating Hodgkin's disease from morphologically similar conditions such as T-cell-rich B-cell lymphoma.

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