Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors

Background: Breast cancer is the most common cancer in women worldwide and is the leading cause of death in women with cancer. One novel therapy used for breast cancer treatment is non-contact electric fields called electro-capacitive cancer therapy (ECCT) with intermediate frequency (100 kHz) and low intensity (18 Vpp). The objective of this study was to examine the effect of ECCT on mammary tumors growth in rats and observing the immune responses that play a role in fighting the tumor. Methods: Female SD rats were used and divided into four groups, namely control (NINT), placebo (NIT), non- therapy (INT), and therapy (IT) groups with 6 biological replicates in each group. Rats in INT and IT groups were treated with 7,12-dimethylbenz[a]anthracene for mammary tumor induction. Only rats in NIT and IT groups were exposed to ECCT individually for 10 hours per day for 21 days. The size of all tumors was measured with a digital caliper. The distributions of PCNA, ErbB2, caspase-3, CD68, CD4 and CD8-positive cells were observed with immunohistochemistry and scoring with ImageJ. Results: The growth rate of mammary tumors in IT group was significantly lower (p<0.05) than that in the INT group. The number of mitotic figures and the percentage of PCNA, caspase-3, and CD68- positive cells in IT group were significantly lower (p<0.05) than those in INT group. Conversely, the percentage of CD8-positive T cells in IT group was significantly higher (p<0.05) than that in INT group. Moreover, the CD4/CD8 ratio in IT group was decreased. Some tumor tissues were blackened and detached from the surrounding tissue, resulting in an open wound which then healed up upon exposure. Conclusions: Non-contact electric fields exposure showed inhibition on mammary tumor growth in rats while inducing CD8+ T cells that lead to tumor cells death and potentially helps wound healing.

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Metabolic modulation of tumors with engineered bacteria for immunotherapy

10.21203/rs.3.rs-500473/v1 ◽

2021 ◽

Author(s):

Roger Geiger ◽

Fernando Canale ◽

Camilla Basso ◽

Gaia Antonini ◽

Michela Perotti ◽

...

Keyword(s):

T Cells ◽

Checkpoint Inhibitors ◽

Synergistic Effects ◽

Waste Product ◽

T Cell Response ◽

Metabolic Modulation ◽

Escherichia Coli Nissle 1917 ◽

Blocking Antibodies ◽

Engineered Bacteria ◽

Escherichia Coli Nissle

Abstract The availability of L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. Consequently, elevation of typically low L-arginine levels within the tumor may greatly potentiate the anti-tumor responses of immune checkpoint inhibitors, such as PD-L1 blocking antibodies. However, currently no means are available to locally increase intra-tumoral L-arginine levels. Here, we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumors and continuously converts ammonia, a metabolic waste product that accumulates in tumors4, into L-arginine. Colonization of tumors with these bacteria elevated intra-tumoral L-arginine concentrations, increased the amount of tumor-infiltrating T cells, and had striking synergistic effects with PD-L1 blocking antibodies in the clearance of tumors. The anti-tumor effect of the living therapeutic was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumor microenvironment leading to enhanced efficacy of immunotherapies.

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The study on the effect of depression on breast cancer incidence through IDO/kynurenine pathway.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13569 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13569-e13569

Author(s):

Yanmei Zhang ◽

Ling Zhu ◽

Dandan Chen ◽

Rui Xu ◽

Liping Ren ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Brain Tissue ◽

Cancer Incidence ◽

Breast Cancer Incidence ◽

Depression Scale ◽

Mammary Tumors ◽

Inflammatory Factors ◽

Clinical Samples ◽

Hamilton Depression Scale

e13569 Background: Psychosocial factors have been considered as the most common causes for women with breast cancer. However, it remains unclear whether mental stress can influence cancer incidence and progression. This study aims to investigate the relationship between them and the potential molecular mechanism. Methods: Depression model was established by restricting MMTV-PyMT mice in a 50ml-fixator for 4 h per day for 21 consecutive days. Behavioral tests including light-dark box test, open-field test and force swimming test were performed. Then blood, brain and mammary samples were collected at the indicated time points. ELISA was used to detect the concentration of neurotransmitters serotonin, epinephrine and norepinephrine and inflammatory factors IL-6, TNF-a and IL-1β in brain tissue and serum. Real-time quantitative qPCR and western blot were used to detect indoleamine 2, 3-dioxygenase (IDO) expression. The level of tryptophan was measured by high performance liquid chromatography(HPLC). Flow cytometry was used to evaluate the exhaustion of CD8+ T cells. Besides, the correlation between IDO expression detected by immunohistochemistry and the severity of mammary tumors was analyzed in the tumor specimens. Results: We observed that chronic stress caused depression-like behaviors, abnormal secretion of neurotransmitters serotonin, epinephrine and norepinephrine and promoted the development of breast cancer in MMTV-PyMT mice. Depression elevated the secretion of inflammatory factors IL-6, TNF-a and IL-1β in brain tissue and serum, which upregulated the expression of IDO and decreased the level of tryptophan in mice. Furthermore, T cells are sensitive to low tryptophan concentration, so elevated IDO expression suppressed and exhausted CD8+ T cells, ultimately promoting cancer incidence. Administration of xiaoyao pill (a well-known Chinese herbal formula for treating depression) or IDO inhibitor reversed the depression-like behaviors in mice and slowed the development of breast cancer. At the same time, the analysis of clinical samples showed that depression identified by Hamilton Depression Scale(HAMD) and IDO expression in mammary tumor tissues were positively correlated with the severity of mammary tumors. Conclusions: Altogether, our results suggest that depression can promote tumor immune privilege and cancer occurrence through inducing upregulated IDO expression.

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Ly phenotype of T cells cytotoxic for syngeneic mouse mammary tumors: evidence for T cell interactions.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.74.12.5667 ◽

1977 ◽

Vol 74 (12) ◽

pp. 5667-5671 ◽

Cited By ~ 33

Author(s):

O. Stutman ◽

F. W. Shen ◽

E. A. Boyse

Keyword(s):

T Cells ◽

T Cell ◽

Mammary Tumors ◽

Cell Interactions ◽

Syngeneic Mouse ◽

Mouse Mammary Tumors

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Mice developing mammary tumors evolve T cell sequences shared with human breast cancer patients

10.1101/371260 ◽

2018 ◽

Cited By ~ 1

Author(s):

Miri Gordin ◽

Hagit Philip ◽

Alona Zilberberg ◽

Moriah Gidoni ◽

Raanan Margalit ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

T Cell ◽

Cancer Patients ◽

Human Breast Cancer ◽

Tumor Development ◽

Mammary Tumors ◽

Cell Receptor ◽

Breast Cancer Patients ◽

Human Breast

AbstractCancer immunotherapy by checkpoint blockade proves that an effective immune response to a tumor can be induced clinically. However, little is known about the evolution of tumor-associated T-cell receptor (TCR) repertoires without intervention. Here we studied TCR repertoire evolution in mice spontaneously developing mammary tumors; we sequenced peripheral blood alpha and beta TCRs of CD4+CD62L+CD44− T cells monthly for 8 months in 10 FVB/NJ mice transgenic at the Erbb2 locus, all developing tumors; 5 FVB/NJ mice without the transgene were age-matched controls. Sequences were either private (restricted to one mouse) or public (shared among mice); public sequences were either exclusive to the tumor group or inclusive among different groups. We now report that 1), public AA sequences were each encoded by many different nucleotide sequences (NT) recombinations (convergent recombination; CR); 2) mice developing tumors evolved tumor-exclusive public sequences, derived initially from private or from inclusive public sequences; and 3) tumor-exclusive public sequences in mice were also present among published public TCR sequences from human breast cancer patients. These cross-species tumor-exclusive TCR sequences manifested high CR; but the AA sequences shared by mice and humans did not share NT sequences. Thus, tumor-exclusive TCR AA sequences across species are selected from different NT recombination events. The roles of tumor-exclusive TCR repertoires in advancing or inhibiting tumor development and the effects of tumor immunotherapy on these T cells remain to be seen.

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Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-021-01455-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Toshihiro Yokoi ◽

Takaaki Oba ◽

Ryutaro Kajihara ◽

Scott I. Abrams ◽

Fumito Ito

Keyword(s):

Breast Cancer ◽

T Cells ◽

Brain Metastases ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Potential ◽

Mammary Tumors ◽

Preclinical Model ◽

Tumor Cell Death ◽

Intralesional Therapy

AbstractDespite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells that mediate the regression of mammary tumors and potentiate anti-PD-1/PD-L1 therapeutic efficacy. However, it remains unknown whether this strategy is effective against metastatic TNBC, which is poorly responsive to immunotherapy. Here, using a mouse model of TNBC, we established orthotopic mammary tumors and brain metastases, and treated mammary tumors with in situ immunomodulation (ISIM) consisting of intratumoral injections of Flt3L to mobilize cDC1s, local irradiation to induce immunogenic tumor cell death, and TLR3/CD40 stimulation to activate cDC1s. ISIM treatment of the mammary tumor increased circulating T cells with effector phenotypes, and infiltration of CD8+ T cells into the metastatic brain lesions, resulting in delayed progression of brain metastases and improved survival. Furthermore, although anti-PD-L1 therapy alone was ineffective against brain metastases, ISIM overcame resistance to anti-PD-L1 therapy, which rendered these tumor-bearing mice responsive to anti-PD-L1 therapy and further improved survival. Collectively, these results illustrate the therapeutic potential of multimodal intralesional therapy for patients with unresectable and metastatic TNBC.

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Intratumoral, Injection of Adenoviral Flt3 Ligand Has Therapeutic Activity in Association with Increased Intratumoral Levels of T Cells but Not Dendritic Cells.

Blood ◽

10.1182/blood.v104.11.5280.5280 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5280-5280

Author(s):

James E. Talmadge ◽

Scott G. Kurz ◽

Randy R. Fields ◽

Devendra K. Agrawal ◽

Rakesh K. Singh ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Fold Increase ◽

Mammary Tumors ◽

Intratumoral Injection ◽

Lymphoid Cells ◽

Mammary Adenocarcinoma ◽

Therapeutic Activity ◽

Primary Tumors ◽

Hematopoietic Stem

Abstract Fms-like tyrosine kinase 3 ligand (Flt3L) is a growth factor for dendritic cells (DCs), hematopoietic stem cells, and natural killer (NK) cells in vivo. Ten daily injections of Flt3L, systemically expands DCs, whereas a single injection of an adenovirus vector with the Flt3L transgene (Adv-Flt3L) significantly expands DCs as soon as 2 days following intravenous (iv) injection. The increases in DC numbers, following iv injection, remains at near peak levels from day 6 through day 16. Maximal DC expansion occurs following the iv injection of 1011 virus particles, such that eight days following the iv injection of Adv-Flt3L it induced an 8 fold increase in splenic CD11c+CD11b−CD8a+ cells (immune augmenting DCs), a 6 fold increase in splenic CD11c+B220+ plasmacytoid DCs, and a 9 fold increase in splenic CD11c+CD11b+ cells (immunosuppressive DCs). The increase in DC numbers and cellularity returns to near normal levels by 22 days following iv injection of Adv-Flt3L. Despite the 2–3 fold increase in spleen cellularity and significant expansion of DCs in the spleen, blood and lungs by the iv injection of Adv-Flt3L, this route of administration has minimal to no therapeutic activity for orthrotopic mammary tumors, even when therapy is initiated against small primary tumors. In contrast, the intratumoral injection of Adv-Flt3L has significant therapeutic activity against orthrotopic mammary tumors including mice in which therapy was initiated against large tumors. Unexpectedly, no significant increase in DC infiltration of the tumor was observed following iv or intratumoral Adv-Flt3L administration. In contrast, the number of tumor infiltrating CD4+ and CD8+ cells was increased following intratumoral but not iv Adv-Flt3L administration, suggesting an association with therapeutic activity. Adv-Flt3L injection also induced DC expansion in the spleen, PB and lungs in cl-66, mammary adenocarcinoma-bearing mice. Injection of adv-Flt3L (iv or intratumoral) also stimulated the expansion of T-cells (both CD4+ and CD8+) and a type 1 T cell response as measured by qRT-PCR. Further, the therapeutic activity and increased mitogenic responses by splenic lymphoid cells to Con-A and IL-2 was not depressed in mice bearing cl-66 tumors and the effect of Adv-Flt3L, while partially associated with the Adv vector, was significantly higher in mice injected with Adv-Flt3L.

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Impact of STAT1 and CD8+T cells on the antineoplastic activity of lapatinib and doxorubicin against spontaneous mammary tumors

OncoImmunology ◽

10.4161/onci.26689 ◽

2013 ◽

Vol 2 (12) ◽

pp. e26689 ◽

Cited By ~ 1

Author(s):

Piotr Tymoszuk ◽

Wolfgang Doppler

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Mammary Tumors ◽

Antineoplastic Activity

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