Emerging immune checkpoints in the tumor microenvironment: Implications for cancer immunotherapy

Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy.

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Targeting the Tumor Microenvironment for a More Effective and Efficient Cancer Immunotherapy

10.3389/978-2-88963-817-8 ◽

2020 ◽

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy

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The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment

Bioactive Materials ◽

10.1016/j.bioactmat.2020.12.010 ◽

2021 ◽

Vol 6 (7) ◽

pp. 1973-1987

Author(s):

Muyue Yang ◽

Jipeng Li ◽

Ping Gu ◽

Xianqun Fan

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy

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Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment

Cancer Cell International ◽

10.1186/s12935-021-02003-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tiecheng Wang ◽

Jiakang Jin ◽

Chao Qian ◽

Jianan Lou ◽

Jinti Lin ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Tumor Immunity ◽

Immune Cells ◽

Target Genes ◽

Target Therapy ◽

Treatment Strategies ◽

Signal Transduction Pathway ◽

Pathway Activation ◽

Immune System Regulation

AbstractAs the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.

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Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽

10.1038/s41388-021-01846-x ◽

2021 ◽

Author(s):

Audrey Lequeux ◽

Muhammad Zaeem Noman ◽

Malina Xiao ◽

Kris Van Moer ◽

Meriem Hasmim ◽

...

Keyword(s):

Tumor Microenvironment ◽

Cancer Immunotherapy ◽

Transcriptional Activity ◽

Immune Cell ◽

Tumor Resistance ◽

Combination Strategy ◽

Immune Effector ◽

Effector Cells ◽

Melanoma Patients ◽

The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

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Peptide Blocking CTLA-4 and B7-1 Interaction

Molecules ◽

10.3390/molecules26020253 ◽

2021 ◽

Vol 26 (2) ◽

pp. 253

Author(s):

Stepan V. Podlesnykh ◽

Kristina E. Abramova ◽

Anastasia Gordeeva ◽

Andrei I. Khlebnikov ◽

Andrei I. Chapoval

Keyword(s):

Cancer Immunotherapy ◽

Functional Activity ◽

Synthetic Peptide ◽

Checkpoint Inhibitors ◽

Specific Interaction ◽

Protein A ◽

Tumor Rejection ◽

Immune Checkpoints ◽

3D Computer Model ◽

Molecular Compounds

Discovery of the B7 family immune checkpoints such as CTLA-4 (CD152), PD-1 (CD279), as well as their ligands B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), and B7-DC (PD-L2, CD273), has opened new possibilities for cancer immunotherapy using monoclonal antibodies (mAb). The blockade of inhibitory receptors (CTLA-4 and PD-1) with specific mAb results in the activation of cancer patients’ T lymphocytes and tumor rejection. However, the use of mAb in clinics has several limitations including side effects and cost of treatment. The development of new low-molecular compounds that block immune checkpoints’ functional activity can help to overcome some of these limitations. In this paper, we describe a synthetic peptide (p344) containing 14 amino acids that specifically interact with CTLA-4 protein. A 3D computer model suggests that this peptide binds to the 99MYPPPY104 loop of CTLA-4 protein and potentially blocks the contact of CTLA-4 receptor with B7-1 ligand. Experimental data confirm the peptide-specific interaction with CTLA-4 and its ability to partially block CTLA-4/B7-1 binding. The identified synthetic peptide can be used for the development of novel immune checkpoint inhibitors that can block CTLA-4 functional activity for cancer immunotherapy.

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Tumor Microenvironment-Triggered In-Situ Cancer Vaccines with Dual Immunogenic Cell Death Inductions for Elevated Antitumor and Antimetastatic Therapy

Nanoscale ◽

10.1039/d1nr02018h ◽

2021 ◽

Author(s):

Jun Lin ◽

Binbin Ding ◽

Pan Zheng ◽

Dong Li ◽

Meifang Wang ◽

...

Keyword(s):

Cell Death ◽

Tumor Microenvironment ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Cancer Vaccines ◽

High Specificity ◽

The Body ◽

Immunogenic Cell Death ◽

Specific Antigens

Cancer vaccine is to make tumor-specific antigens into vaccines, which then are injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic...

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836 Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0836 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A888-A888

Author(s):

Laura Ridgley ◽

Angus Dalgleish ◽

Mark Bodman-Smith

Keyword(s):

T Cells ◽

Cancer Immunotherapy ◽

Tumour Cell ◽

Immune Checkpoint ◽

Expansion Method ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Inhibitory Receptors ◽

Healthy Donors ◽

Vγ9vδ2 T Cells

BackgroundVγ9Vδ2 T-cells are a subset of cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses, often exploited in cancer immunotherapy. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of activatory and inhibitory markers on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy.MethodsPBMCs were isolated from healthy donors and the expression of activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry at baseline, following 24 hours activation and 14 days expansion using zoledronic acid (ZA) and Bacillus Calmette-Guerin (BCG), both with IL-2. Activation and expansion of Vδ2 cells was assessed by expression of CD69 and by frequency of Vδ2 cells, respectively. Production of effector molecules was also assessed following coculture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also assessed.ResultsVγ9Vδ2 T-cells constitutively expressed high levels of NK-associated activatory markers NKG2D and DNAM1 which remained high following stimulation with ZA and BCG. Vγ9Vδ2 T-cells expressed variable levels of checkpoint inhibitor molecules at baseline with high levels of BTLA, KLRG1 and NKG2A and intermediate levels of PD1, TIGIT and VISTA. Expression of checkpoint receptors were modulated following activation and expansion with ZA and BCG with decreased expression of BTLA and upregulation of numerous markers including PD1, TIGIT, TIM3, LAG3 and VISTA. Expression of these markers is further modulated upon coculture with tumour cell lines with changes reflecting activation of these cells with Vγ9Vδ2 T-cells expressing inhibitory receptors PD1 and NKG2A producing the highest level of TNF.ConclusionsOur data reveals unique characteristics of Vδ2 in terms of their expression of immune checkpoints, which provide a mechanism which may be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. Our work suggests different profiles of immune checkpoints dependent on the method of stimulation. This highlights importance of expansion method in the function of Vγ9Vδ2 T-cells. Furthermore, this work suggests important candidates for blockade by immune checkpoint therapy in order to increase the successful use of Vγ9Vδ2 T-cells in cancer immunotherapy.

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