scholarly journals Topical arginase inhibition decreases growth of cutaneous squamous cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amit Mittal ◽  
Mike Wang ◽  
Aurobind Vidyarthi ◽  
Diana Yanez ◽  
Gabriela Pizzurro ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Squamous Cell ◽  
Therapeutic Potential ◽  
Chemical Carcinogenesis ◽  
Therapeutic Modality ◽  
Tumor Growth Inhibition ◽  
Tumor Infiltration ◽  
Mouse Keratinocytes ◽  
Immunocompetent Mice

AbstractCutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.

scholarly journals A nanoparticle vaccine that targets neoantigen peptides to lymphoid tissues elicits robust antitumor T cell responses

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Carlos A. Arbelaez ◽  
Juan Estrada ◽  
Melissa A. Gessner ◽  
Charles Glaus ◽  
Agnieszka B. Morales ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Tumor Antigens ◽  
T Cell Responses ◽  
Tumor Growth Inhibition ◽  
Lymphoid Tissues ◽  
Dependent Manner ◽  
Kras Mutations ◽  
Peptide Antigens ◽  
Cell Responses

AbstractCancer vaccines using synthetic long peptides (SLP) targeting tumor antigens have been tested in the clinic but the outcomes have been unimpressive, perhaps because these peptides elicit predominantly CD4+ T cell responses. We hypothesized that enhanced delivery of peptide antigens to, and uptake in, secondary lymphoid tissues should elicit more robust CD8+ and CD4+ T cell responses and improved anti-tumor responses. Here, we have designed SLP-containing cationic lipoplexes (SLP–Lpx) that improve delivery of peptides to myeloid cells in the spleen and lymphatics. Using the G12D KRAS mutations as neoantigens, we found that vaccination of mice with naked synthetic peptides harboring the G12D mutation with CpG adjuvant stimulated mainly CD4+ T cell responses with limited tumor growth inhibition. On the other hand, immunization with SLP–Lpx stimulated both CD4+ and CD8+ T cells and suppressed tumor growth in a CD8+ T cell-dependent manner. Combination of the SLP–Lpx vaccines with a checkpoint inhibitor led to profound growth suppression of established tumors. These studies suggest that preferential targeting of peptides derived from neoantigens to the spleen via lipoplexes elicits potent CD4+ and CD8+ T cell responses that inhibit tumor growth.

scholarly journals Tumor growth inhibition by mSTEAP peptide nanovaccine inducing augmented CD8+ T cell immune responses

2019 ◽  
Vol 9 (6) ◽  
pp. 1095-1105 ◽  
Author(s):  
Qiuqiang Chen ◽  
Ying Bao ◽  
Danielle Burner ◽  
Sharmeela Kaushal ◽  
Yu Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Cd8 T Cell ◽  
Tumor Growth Inhibition ◽  
T Cell Immune Responses

Do dendritic cells hold the key to regulating cancer antitumor immunity?

2020 ◽  
Vol 12 (551) ◽  
pp. eabd3081
Author(s):  
Ecaterina Ileana-Dumbrava
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Antitumor Immunity ◽  
T Cell Responses ◽  
Tumor Growth Inhibition ◽  
Cell Responses

PD-L1 blockage on dendritic cells, but not macrophages, may enhance antitumor or CD8+ T cell responses leading to greater tumor growth inhibition.

scholarly journals Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Junko Matsuzaki ◽  
Takemasa Tsuji ◽  
Immanuel F. Luescher ◽  
Hiroshi Shiku ◽  
Junichi Mineno ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Cell Subset ◽  
Cd4 T Cell ◽  
Tumor Growth Inhibition ◽  
T Cell Subset ◽  
Tumor Recognition

scholarly journals 4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Subhankar Panda ◽  
Nirmalya Pradhan ◽  
Soumya Chatterjee ◽  
Sudhir Morla ◽  
Abhishek Saha ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cell Activity ◽  
Tumor Growth Inhibition ◽  
Structural Class ◽  
Cell Functions ◽  
Indoleamine 2,3 Dioxygenase ◽  
Potential Applications

AbstractThe improvement of body’s own immune system is considered one of the safest approaches to fight against cancer and several other diseases. Excessive catabolism of the essential amino acid, L-tryptophan (L-Trp) assists the cancer cells to escape normal immune obliteration. The formation of disproportionate kynurenine and other downstream metabolites suppress the T cell functions. Blocking of this immunosuppressive mechanism is considered as a promising approach against cancer, neurological disorders, autoimmunity, and other immune-mediated diseases. Overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is directly related to the induction of immunosuppressive mechanisms and represents an important therapeutic target. Several classes of small molecule-based IDO1 inhibitors have been already reported, but only few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In the quest for novel structural class(s) of IDO1 inhibitors, we developed a series of 4,5-disubstituted 1,2,3-triazole derivatives. The optimization of 4,5-disubstituted 1,2,3-triazole scaffold and comprehensive biochemical and biophysical studies led to the identification of compounds, 3i, 4i, and 4k as potent and selective inhibitors of IDO1 enzyme with IC50 values at a low nanomolar level. These potent compounds also showed strong IDO1 inhibitory activities in MDA-MB-231 cells with no/negligible level of cytotoxicity. The T cell activity studies revealed that controlled regulation of IDO1 enzyme activity in the presence of these potent compounds could induce immune response against breast cancer cells. The compounds also showed excellent in vivo antitumor efficacy (of tumor growth inhibition = 79–96%) in the female Swiss albino mice. As a consequence, this study describes the first example of 4,5-disubstituted 1,2,3-triazole based IDO1 inhibitors with potential applications for immunotherapeutic studies.

scholarly journals Lactate Increases Stemness of CD8+ T Cells to Augment Anti-Tumor Immunity

2021 ◽  
Author(s):  
Qiang Feng ◽  
Zhida Liu ◽  
Xuexin Yu ◽  
Tongyi Huang ◽  
Jiahui Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Subcutaneous Administration ◽  
Tumor Growth Inhibition ◽  
Mouse Splenocytes

Nutrients and metabolites play important roles in immune functions. Recent studies show lactate instead of glucose can serve as a primary carbon fuel source for most tissues. The role of lactate in tumor immunity is not well understood with immune suppressive functions reported for lactic acid, the conjugate acid form of lactate. In this study, we report lactate increases the stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of lactate but not glucose shows CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis revealed lactate treatment increased a subpopulation of stem-like TCF-1-expressing CD8+ T cells, which is further validated by ex vivo culture of CD8+ T cells from mouse splenocytes and human peripheral blood mononuclear cells. The inhibition of histone deacetylase activity by lactate increased acetylation in the histone H3K27 site at the Tcf7 super enhancer locus and increased the gene expression of Tcf7. Adoptive transfer of CD8+ T cells pretreated with lactate in vitro showed potent tumor growth inhibition in vivo. Our results elucidate the immune protective role of lactate in anti-tumor immunity without the masking effect of acid. These results may have broad implications for T cell therapy and the understanding of lactate in immune metabolism.

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