Abstract 3547: Disruption of Galectin1-glycan interaction impairs tumor growth and metastasis in breast cancer by disarming the immunosuppressive capacity of regulatory T cells

AbstractMice reconstituted with a human immune system and bearing human tumors represent a promising model for developing novel cancer immunotherapies. Here, we used mass cytometry and multi-parametric flow cytometry to characterize human leukocytes infiltrating a human breast cancer tumor model in immunocompromised NOD.SCID.γc-null mice reconstituted with a human immune system and compared it to samples of breast cancer patients. We observed highly activated human CD4+ and CD8+ T cells in the tumor, as well as minor subsets of innate immune cells in both settings. We also report that ICOS+ CD4+ regulatory T cells (Treg) were enriched in the tumor relative to the periphery in humanized mice and patients, providing a target to affect Treg and tumor growth. Indeed, administration of a neutralizing mAb to human ICOS reduced Treg proportions and numbers and improved CD4+ T cell proliferation in humanized mice. Moreover, a combination of the anti-ICOS mAb with cyclophosphamide reduced tumor growth, and that was associated with an improved CD8 to Treg ratio. However, depletion of human CD8+ T cells only marginally affected tumor control whereas depletion of murine myeloid cells abrogated the effect of the combination therapy. Altogether, our results indicate that a combination of anti-ICOS mAb and chemotherapy controls tumor growth in humanized mice and highlight the crucial implication of innate immunity in treatment efficacy, opening new perspectives for the treatment of breast cancer.One sentence summaryICOS expressed on Tregs is a promising target to improve tumor immunity in humansAbbreviationsICOSInducible CostimulatoryNSGNOD.SCID.gc-nullTregregulatory T cellsCTXcyclophosphamideHuMicehumanized miceCyTOFcytometry time-of-flighttSNEtdistributed stochastic neighbor embeddingpDCsplasmacytoid dendritic cellsDCdendritic cellsICDimmunogenic cell death

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Role of the Tyrosine Phosphatase SHP-1 and Regulatory T Cells in Breast Cancer

10.21236/ada501068 ◽

2008 ◽

Author(s):

Ulrike Lorenz

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Tyrosine Phosphatase

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Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02872-0 ◽

2021 ◽

Cited By ~ 1

Author(s):

Shasha Liu ◽

Chaoqi Zhang ◽

Boqiao Wang ◽

Huanyu Zhang ◽

Guohui Qin ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Tumor Growth ◽

Xenograft Model ◽

Malignant Growth ◽

Cancer Stemness ◽

The Core ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Tumorigenic Potential

AbstractGlioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB–IL6–STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.

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Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22105207 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5207

Author(s):

Chi Yan ◽

Jinming Yang ◽

Nabil Saleh ◽

Sheau-Chiann Chen ◽

Gregory D. Ayers ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Tumor Growth ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Mtor Pathway ◽

Complete Regression ◽

Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

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