scholarly journals Hydroxychloroquine (HCQ) reverses anti-PD-1 immune murine checkpoint blockade: TCF1 as a marker in humans for COVID-19 and HCQ therapy

2020 ◽  
Author(s):  
Janna Kreuger ◽  
Francois Santinon ◽  
Alexandra Kazanova ◽  
Mark Issa ◽  
Bruno Larrivee ◽  
...  
Keyword(s):  
Public Health ◽  
T Cells ◽  
Cd8 T Cells ◽  
Deleterious Effect ◽  
Therapeutic Benefit ◽  
Tumor Rejection ◽  
Checkpoint Blockade ◽  
Global Public Health ◽  
Melanoma Tumor ◽  
First Time

Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to global public health. Hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZ) are still being used by thousands and numerous hospitals to treat COVID-19. In a related context, immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised cancer therapy. Given that cancer patients on ICB continue to be infected with SARS-CoV-2, an understanding of the effects of HCQ and AZ on the elimination of tumors by anti-PD-1 ICB is urgently needed. In this study, we report that HCQ alone, or in combination with AZ, at doses used to treat COVID-19 patients, reverses the therapeutic benefit of anti-PD-1 in controlling B16 melanoma tumor growth in mice. No deleterious effect was seen on untreated tumors, or in using AZ alone in anti-PD-1 immunotherapy. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor-infiltrating T-cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also blocked the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T-cells, FoxP3+ Tregs, thymic subsets, B-cells, antibody production, myeloid cells, or the vasculature of mice. Lastly, we identified TCF-1 expression in peripheral CD8+ T-cells from cancer or non-cancer human patients infected with SARs CoV2 as a marker for the effects of COVID-19 and HCQ on the immune system. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.

scholarly journals Hydroxychloroquine (HCQ) decreases the benefit of anti-PD-1 immune checkpoint blockade in tumor immunotherapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0251731
Author(s):  
Janna Krueger ◽  
Francois Santinon ◽  
Alexandra Kazanova ◽  
Mark E. Issa ◽  
Bruno Larrivee ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Lupus Erythematosus ◽  
Deleterious Effect ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Tumor Rejection ◽  
Checkpoint Blockade ◽  
Systemic Lupus ◽  
First Time

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.

scholarly journals Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade

2019 ◽  
Vol 20 (3) ◽  
pp. 326-336 ◽  
Author(s):  
Brian C. Miller ◽  
Debattama R. Sen ◽  
Rose Al Abosy ◽  
Kevin Bi ◽  
Yamini V. Virkud ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Checkpoint Blockade ◽  
Tumor Control

scholarly journals A reassessment of the role of B7-1 expression in tumor rejection.

1995 ◽  
Vol 182 (5) ◽  
pp. 1415-1421 ◽  
Author(s):  
T C Wu ◽  
A Y Huang ◽  
E M Jaffee ◽  
H I Levitsky ◽  
D M Pardoll
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Tumor Rejection ◽  
Type B ◽  
Wild Type ◽  
Systemic Immunity ◽  
Murine Tumor

Introduction of the B7-1 gene into murine tumor cells can result in rejection of the B7-1 transductants and, in some cases, systemic immunity to subsequent challenge with the nontransduced tumor cells. These effects have been largely attributed to the function of B7-1 as a costimulator in directly activating tumor specific, major histocompatibility class I-restricted CD8+ T cells. We examined the role of B7-1 expression in the direct rejection as well as in the induction of systemic immunity to a nonimmunogenic murine tumor. B-16 melanoma cells with high levels of B7-1 expression did not grow in C57BL/6 recipient mice, while wild-type B-16 cells and cells with low B7-1 expression grew progressively within 21 d. In mixing experiments with B7-1hi and wild-type B-16 cells, tumors grew out in vivo even when a minority of cells were B7-1-. Furthermore, the occasional tumors that grew out after injection of 100% B-16 B7-1hi cells showed markedly decreased B7-1 expression. In vivo antibody depletions showed that NK1.1 and CD8+ T cells, but not CD4+ T cells, were essential for the in vivo rejection of tumors. Animals that rejected B-16 B7-1hi tumors did not develop enhanced systemic immunity against challenge with wild-type B-16 cells. These results suggest that a major role of B7-1 expression by tumors is to mediate direct recognition and killing by natural killer cells. With an intrinsically nonimmunogenic tumor, this direct killing does not lead to enhanced systemic immunity.

PD-1 blockade and vaccination provide therapeutic benefit against SIV by inducing broad and functional CD8 + T cells in lymphoid tissue

2021 ◽  
Vol 6 (63) ◽  
Author(s):  
Sheikh Abdul Rahman ◽  
Bhrugu Yagnik ◽  
Alexander P. Bally ◽  
Kristen N. Morrow ◽  
Shelly Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Lymphoid Tissue ◽  
Therapeutic Benefit

Regulation of Tim-3 function by binding to phosphatidylserine

2021 ◽  
Vol 478 (22) ◽  
pp. 3999-4004
Author(s):  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Cytotoxic T Cells ◽  
Cross Presentation ◽  
First Time

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

scholarly journals Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2762 ◽  
Author(s):  
Xinrui Zhao ◽  
Chunlin Shao
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Combined Therapy ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Abscopal Effect ◽  
Specific Circumstance

Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the “hot” tumors gradually turn to “cold”. With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic.

scholarly journals Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Asiel A. Benitez ◽  
Sara Khalil-Agüero ◽  
Anjali Nandakumar ◽  
Namita T. Gupta ◽  
Wen Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Tumor Rejection ◽  
Checkpoint Blockade ◽  
Cell Repertoire ◽  
Activated T Cells ◽  
Central Tolerance ◽  
Tolerance Breakdown ◽  
Deficient Mice

AbstractThe endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire’s central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.

scholarly journals Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells

2005 ◽  
Vol 202 (7) ◽  
pp. 885-891 ◽  
Author(s):  
Kuibeom Ko ◽  
Sayuri Yamazaki ◽  
Kyoko Nakamura ◽  
Tomohisa Nishioka ◽  
Keiji Hirota ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Effector T Cells ◽  
Tumor Rejection ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Ifn Γ ◽  
Advanced Tumors

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family–related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-γ–secreting cells, infiltrated regressing tumors. Tumor-specific IFN-γ–secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-γ–intact mice but not IFN-γ–deficient mice. Furthermore, coadministration of anti-GITR and anti–CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg–specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg–mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-γ, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

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