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.

Agonist anti-GITR antibody induces CD8 T cell-mediated tumor rejection

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3058-3058
Author(s):  
A. D. Cohen ◽  
A. Diab ◽  
M. A. Perales ◽  
F. Duan ◽  
R. Jenq ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Tumor Antigens ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Tumor Rejection ◽  
Cd8 Cells

3058 Background: Signaling through GITR (glucocorticoid-induced tumor necrosis factor receptor) can abrogate the suppressive effects of CD4+foxp3+ regulatory T cells and co-stimulate activated effector CD4+ and CD8+ T cells. We have previously shown that in vivo GITR ligation using the agonist anti-GITR mAb DTA-1 augments concomitant immunity and immunity generated by active immunization with self- tumor antigens. In the present study, we assessed the activity of anti-GITR mAb used alone, focusing on the effects of GITR ligation on CD8+ T cells during tumor growth. Methods: C57BL/6 mice were injected intradermally with B16 melanoma and received 1mg of DTA-1 or control rat IgG intraperitoneally on various days after tumor injection. In some experiments, naïve, CFSE-labeled pmel-1 CD8+ transgenic T cells (specific for the melanoma antigen gp10025–33 epitope) were transferred into naïve recipients 1 day prior to B16 inoculation. Results: DTA-1 treatment on days 0 and 4 led to tumor rejection in 20–30% and 50–60% of mice, respectively, compared with rejection in 0–5% of mice treated with control IgG (p<0.05 for both). Treatment at day 7 or later had no significant impact on tumor-free survival. The importance of CD8+ T cells in mediating DTA-1-induced tumor immunity was demonstrated by 4 findings: 1) in untreated mice, tumor-infiltrating CD8+ lymphocytes significantly upregulated GITR expression during tumor growth; 2) DTA-1-treated mice had greater CD8+ T cell infiltration into tumors than IgG-treated mice; 3) depletion of CD8+ cells completely abrogated the tumor protection provided by DTA-1; and 4) tumor-specific CD8+ cells proliferated more extensively, became more activated, and exhibited greater effector function following DTA-1 administration compared with control IgG. This was most dramatically seen within the tumor (compared with spleen or draining lymph node), suggesting that a major mechanism of tumor immunity induced by anti-GITR mAb may be overcoming impaired CD8+ T cell function within the tumor microenvironment. Conclusions: Ligating GITR using an agonist mAb can by itself augment tumor-specific CD8+ T cell responses and induce rejection of an aggressive, poorly immunogenic tumor. This strategy merits further consideration as an immune-modulating therapy for cancer. No significant financial relationships to disclose.

scholarly journals The anti-tumor effects of cetuximab in combination with VTX-2337 are T cell dependent

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yinwen Cheng ◽  
Nicholas Borcherding ◽  
Ayomide Ogunsakin ◽  
Caitlin D. Lemke-Miltner ◽  
Katherine N. Gibson-Corley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Syngeneic Mouse ◽  
T Cell Infiltration ◽  
Cancer Immunotherapeutic

AbstractThe Toll-like receptor 8 (TLR8) agonist VTX-2337 (motolimod) is an anti-cancer immunotherapeutic agent that is believed to augment natural killer (NK) and dendritic cell (DC) activity. The goal of this work is to examine the role of TLR8 expression/activity in head and neck squamous cell carcinoma (HNSCC) to facilitate the prediction of responders to VTX-2337-based therapy. The prognostic role of TLR8 expression in HNSCC patients was assessed by TCGA and tissue microarray analyses. The anti-tumor effect of VTX-2337 was determined in SCCVII/C3H, mEERL/C57Bl/6 and TUBO-human EGFR/BALB/c syngeneic mouse models. The effect of combined VTX-2337 and cetuximab treatment on tumor growth, survival and immune cell recruitment was assessed. TLR8 expression was associated with CD8+ T cell infiltration and favorable survival outcomes. VTX-2337 delayed tumor growth in all 3 syngeneic mouse models and significantly increased the survival of cetuximab-treated mice. The anti-tumor effects of VTX-2337+ cetuximab were accompanied by increased splenic lymphoid DCs and IFNγ+ CD4+ and tumor-specific CD8+ T cells. Depletion of CD4+ T cells, CD8+ T cells and NK cells were all able to abolish the anti-tumor effect of VTX-2337+ cetuximab. Altogether, VTX-2337 remains promising as an adjuvant for cetuximab-based therapy however patients with high TLR8 expression may be more likely to derive benefit from this drug combination compared to patients with low TLR8 expression.

scholarly journals Knockout of High-Mobility Group Box 1 in B16F10 Melanoma Cells Induced Host Immunity-Mediated Suppression of In Vivo Tumor Growth

2021 ◽  
Author(s):  
Kanako Yokomizo ◽  
Kayoko Waki ◽  
Miyako Ozawa ◽  
Keiko Yamamoto ◽  
Sachiko Ogasawara ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
High Mobility

Abstract High mobility group box 1 (HMGB1) has been reported as a damage-associated molecular pattern (DAMP) molecule that is released from damaged or dead cells and induces inflammation and subsequent innate immunity. However, the role of HMGB1 in the anti-tumor immunity is unclear since inflammation in the tumor microenvironment also contributes to tumor promotion and progression. In the present study, we established HMGB1-knockout clones from B16F10 and CT26 murine tumors by genome editing using the CRISPR/Cas9 system and investigated the role of HMGB1 in anti-tumor immunity. We found that 1) knockout of HMGB1 in the tumor cells suppressed in vivo, but not in vitro, tumor growth, 2) the suppression of the in vivo tumor growth was mediated by CD8 T cells, and 3) infiltration of CD8 T cells, macrophages and dendritic cells into the tumor tissues was accelerated in HMGB1-knockout tumors. These results demonstrated that knockout of HMGB1 in tumor cells converted tumors from poor infiltration of immune cells called “cold” to “immune-inflamed” or “hot” and inhibited in vivo tumor growth mediated by cytotoxic T lymphocytes. Infiltration of immune cells to the tumor microenvironment is an important step in the series known as the cancer immunity cycle. Thus, manipulation of tumor-derived HMGB1 might be applicable to improve the clinical outcomes of cancer immunotherapies, including immune checkpoint blockades and cancer vaccine therapies.

scholarly journals 208 RTX-224, an engineered allogeneic red cell therapeutic expressing 4–1BBL and IL-12, activates immune cells in blood and spleen to promote tumor growth inhibition in mice

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A219-A219
Author(s):  
Anne-Sophie Dugast ◽  
Shannon McArdel ◽  
Zafira Castano ◽  
Maegan Hoover ◽  
Arjun Reddy Bollampalli ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Nk Cells ◽  
Mechanism Of Action ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cell Types ◽  
Tumor Growth Inhibition ◽  
Tumor Bearing

BackgroundAgonist antibodies and recombinant cytokines have had limited success in the clinic due to three factors: severe toxicity leading to a narrow therapeutic index, the diminished activity of an agonistic antibody compared with natural ligand, and the lack of multiple signals needed to effectively activate most cell types. To address these limitations, Rubius Therapeutics has developed RTX-224, an allogeneic red cell therapeutic genetically engineered to express hundreds of thousands of copies of 4-1BBL and IL-12 in their natural conformation on the cell surface. RTX-224 is designed to activate four key target cell types: CD4+ and CD8+ T cells, antigen presenting cells and NK cells for a broad and effective anti-tumor response while providing improved safety due to the restricted biodistribution of red blood cells to the vasculature and spleen. Here we investigated the potential efficacy and mechanism of action of RTX-224 using the mouse surrogate mRBC-224.MethodsmRBC-224 was administered intravenously (i.v.) to normal or tumor-bearing mice (B16F10 tumor models). Blood, spleen and tumors were harvested and the pharmacodynamic effects of mRBC-224 on immune cells were evaluated.ResultsmRBC-224 administered to mice inoculated i.v. with B16F10 melanoma reduced the number of metastases (p<0.0001 and 76.8% tumor growth inhibition on Day 14). This was accompanied by increased proliferation (Ki67+) and cytotoxicity (GzmB+) of tumor-infiltrating CD8+ T cells and NK cells, and an increased CD8+ effector memory (TEM) phenotype. Similarly, mRBC-224 reduced tumor growth in the B16F10 s.c. model (p<0.0001 and 56.2% tumor growth inhibition on Day 9), and this was associated with increased frequency of activated (MHC-II+) tumor-infiltrating macrophages. Consistent with the known biodistribution of red cells, mRBC-224 did not distribute to the tumor but was predominantly localized in the blood and spleen raising the question about mRBC-224 mechanism of action in mediating antitumor responses. In normal and B16F10 s.c. tumor-bearing mice, mRBC-224 induced the activation of CD8+ T cells, NK cells and monocytes/macrophages in blood and spleen in a dose-dependent manner. PD studies in the tumor suggest that these activated immune cells are capable of trafficking from blood/spleen to the tumor. These results align with published data suggesting that activated T cells in the spleen or blood can replenish exhausted tumor-infiltrating cells.ConclusionsTaken together, these data unveil the mechanism of action of mRBC-224 and suggest that mRBC-224 activate immune cells in the spleen and blood, leading to their trafficking into the tumor microenvironment to promote efficacy.

Diverse Roles of Macrophage Matrix Metalloproteinases in Tissue Destruction and Tumor Growth

1999 ◽  
Vol 82 (08) ◽  
pp. 846-849 ◽  
Author(s):  
Steven Shapiro
Keyword(s):  
Tumor Growth ◽  
Growth Inhibition ◽  
Gene Targeting ◽  
Critical Role ◽  
Human Biology ◽  
Disease Models ◽  
Tumor Growth Inhibition ◽  
Mouse Macrophage ◽  
Tissue Destruction

SummaryIn the mouse, macrophage elastase is critical to macrophage proteolysis. The use of gene-targeting has uncovered both pathological roles, including destructive effects in aneurysm formation and emphysema, and physiological roles, such as tumor growth inhibition and regulation of inflammation. Translation of findings from mouse to human biology depends upon how well the disease models replicate the human conditions and the similarity of enzyme profile between species. We know that human MMP-12 is associated with these diseases, but as opposed to the mouse, other MMPs may also be of importance (MMP-9, and perhaps MMP-7, in particular). Our interpretation is that findings in mice reflect the critical role of macrophage proteolysis in these disease processes.

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