scholarly journals 870 Targeting GCN2 kinase-driven stress response inactivation to restore tumor immunity in metastatic triple negative breast cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A911-A911
Author(s):  
Hariprasad Vankayalapati ◽  
Kyle Medley ◽  
Zhaoliang Li ◽  
Dongqing Yan ◽  
David Bearss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Amino Acids ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Small Molecule ◽  
Triple Negative ◽  
Nutrient Stress ◽  
List Type

BackgroundPatients with PD-L1-positive metastatic triple-negative breast cancers (mTNBC) who have been treated with atezolizumab+nab-paclitaxel had a clinically meaningful overall survival extension of 9.5 months compared to nab-paclitaxel alone, although overall survival in overall population was not statistically significant. Unlike many other cancers, immunotherapy for breast cancer has had limited success, due to the fact that there are very few T cells in the tumor microenvironment of mTNBC patients. Identifying ways to boost immunotherapy responses could change the paradigm of mTNBC, a disease still difficult to treat. The highly proliferative nature of tumor cells, along with infiltration of myeloid cells into the tumors, leads to depletion of nutrients such as functional/natural amino acids. This metabolically stressful milieu causes activation of nutrient stress pathways, autophagy, and repressed immune responses. A key meditator of this nutrient stress pathway is a cytoplasmic Ser/Thr protein kinase called General Control Nonderepressible 2 (GCN2), also called EIF2AK4. GCN2 switches on following reduction of amino acids, and its activity results in T cell inactivation, T cell death, regulatory T cell expansion, and the potentiation of myeloid-derived suppressor cells (MDSCs).MethodsWe have developed and synthesized a series of novel small molecule immunotherapeutic agents that reversibly bind to GCN2 kinase, competitively block the ATP site, and elicit pharmacological responses in immune cells and in breast cancer cells.ResultsGCN2 cell-free kinase binding, kinome selectivity, pGCN2, pEIF2α, ATF-4 phosphorylation inhibition assays were performed. We confirmed on-target efficacy and tested the potency of our lead GCN2 inhibitor HCI-1046. HCI-1046 demonstrated potent activity, with an IC50 of 36 nM in inhibiting GCN2 kinase and exhibited cellular efficacy with an IC50 of 0.1 to 1.0 μM range. Our preliminary results support the hypothesis that the inhibition of GCN2 reinstates anti-tumor immunity and blocks tumor progression in breast cancer models. In vivo PK studies of HCI-1046 in rodents showed excellent PK properties; 55% oral bioavailability, low clearance, and >5 hour half-life.ConclusionsThus, HCI-1046 is nominated as a pre-clinical agent. Additional data regarding evaluation of the effects of HCI-1046 on the MDSC-suppressive function on T cells using ELISpot assays with breast cancer patient samples, and mouse model efficacy studies will be discussed.ReferencesEkiz HA, Lai SA, Gundlapalli H, Haroun F, Williams MA, Welm AL. Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth. Oncoimmunology 2018;7(9):e1480286.Toogood PL. Small molecule immuno-oncology therapeutic agents. Bioorg Med Chem Lett 2018;28(3):319–329.Ravindran R, Loebbermann J, Nakaya HI, Khan N, Ma H, Gama L, Machiah DK, Lawson B, Hakimpour P, Wang YC, Li S, Sharma P, Kaufman RJ, Martinez J, Pulendran B. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature 2016;531(7595):523–527.Brazeau JF, Rosse G. Triazolo[4,5-d]pyrimidine derivatives as inhibitors of GCN2. ACS Med Chem Lett 2014;5(4):282–3.

scholarly journals An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer

2019 ◽  
Vol 11 (513) ◽  
pp. eaax9364 ◽  
Author(s):  
Yin Wu ◽  
Fernanda Kyle-Cezar ◽  
Richard T. Woolf ◽  
Cristina Naceur-Lombardelli ◽  
Julie Owen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Γδ T Cell ◽  
Human Breast ◽  
Cell Compartment ◽  
Αβ T Cells

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αβ T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αβ TCRs. However, whereas in most cases TCRαβ repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αβ T cells.

scholarly journals Nomogram Personalizes and Visualizes the Overall Survival of Patients with Triple-Negative Breast Cancer Based on the Immune Genome

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Peipei Wang ◽  
Yang Fu ◽  
Yueyun Chen ◽  
Qing Li ◽  
Ye Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Risk Score ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Novel Therapy ◽  
Immune Biomarkers ◽  
Poorly Differentiated ◽  
Immune Related Genes

Background. Triple-negative breast cancer (TNBC) is usually poorly differentiated, highly invasive, susceptible to distant metastasis, and less responsive to endocrine and targeted therapy. However, immunotherapy is a promising treatment for TNBC patients recently. Methods. The prognostic value of immune-related genes (IRGs) was explored by using RNA sequencing and microarray data of 123 and 107 TNBC patients from TCGA and GEO databases, respectively. Results. In TCGA database, GO and KEGG pathway analysis of 119 differential IRGs indicated that they actively participate in the interaction of cytokines and receptors. A nomogram model constructed by the prognosis-related CCL25, IL29, TDGF3, GPR44, and GREM2 in the IRGs could personalize and visualize the 1-, 2-, 3-, 4-, and 5-year overall survival (OS) of TNBC patients. Moreover, TNBC patients could be defined as low-risk ( risk   score < 194 ) or high-risk ( risk   score ≥ 194 ) cohorts based on the risk score derived from the nomogram model. The results could be validated by the GSE58812 dataset. Furthermore, the risk score was an independent risk factor for TNBC patients ( HR = 1.019 , 95% CI 1.012-1.027, p < 0.001 ) and was positively related to stage ( p = 0.017 ). Interestingly, the risk score could reflect the infiltration of B cells, CD4+ T cells, CD8+ T cells, dendritic cells, and neutrophils. Conclusion. These findings provided a reference for personalized OS prediction in TNBC patients and might be potential immune biomarkers for designing novel therapy.

Therapeutic effect of local Interleukin-15 with radiotherapy in breast cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 158-158
Author(s):  
Elena Garcia Martinez ◽  
Karsten A Pilones ◽  
Joseph Aryankalayil ◽  
Silvia Formenti ◽  
Sandra Demaria
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Therapeutic Effect ◽  
Tumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Control ◽  
Complete Regression ◽  
Growth And Survival

158 Background: Interleukin (IL)-15 is a key regulator of T cell homeostasis with activity in cancer and a favorable toxicity profile compared to IL-2. IL-15 stimulates the proliferation and effector differentiation of CD8+T cells, and the proliferation and activation of natural killer (NK) cells. We observed IL-15 upregulation by gene arrays in radiotherapy (RT)-treated TSA mouse breast cancer, suggesting that it may play a role in RT-induced anti-tumor immunity. However, the upregulation was modest prompting us to test the hypothesis that administration of IL-15 may enhance in situ vaccination by RT. Methods: BALB/c mice with established poorly immunogenic TSA tumors were sham-treated, treated with tumor-targeted RT (8GyX3 days), IL-15 given peri-tumorally (2 ug/mouse/day for 10 days) starting on the first day of RT, and RT+IL-15, and monitored for tumor growth and survival. Tumor infiltrating lymphocytes (TIL) were analyzed by flow cytometry and immunostaining. In some experiments, Batf3-/-mice were used as tumor recipient. Results: IL-15 by itself was ineffective, but it significantly increased tumor control by RT (p=0.0007, RT versus RT+IL-15) leading to complete responses in 50% of the mice, most of them durable. Analysis of TILs showed significantly increased NK cells (CD45+ CD3- DX5+) in tumors treated with RT+IL-15 (p<0.0004 versus sham-treated; p<0.02 versus RT). NK cells were also more activated as indicated by expression of CD122 and CD137. Depletion of NK cells completely abrogated the therapeutic effect of the combination, while CD8 T cell depletion reduced tumor control and rate of complete regression. Interestingly, Batf3-/- mice, which lack CD103+ DCs, showed reduced response to RT+IL-15 compared to WT mice. Conclusions: Data suggest that local IL-15 with RT is an effective strategy to induce anti-tumor immunity to poorly immunogenic breast cancer. NK cells are critical mediators of the response, and may act by both killing tumor cells and promoting priming of CD8 T cells. Experiments are ongoing to determine the mechanisms of durable complete responses. <footer>Acknowledgments: IL-15 was provided by NCI BRB. Garcia-Martinez E was supported by GEICAM grant.</footer>

WNT/β–catenin pathway activation correlates with the increase of tumor-associated macrophages in triple negative breast cancer (TNBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12564-e12564
Author(s):  
Eleonora Timperi ◽  
Mengliang Ye ◽  
Thierry Dubois ◽  
Didier Meseure ◽  
Anne Vincent- Salomon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Early Stage ◽  
Immune Checkpoint Blockade ◽  
Tumor Associated Macrophages ◽  
T Cell Exclusion

e12564 Background: Triple negative breast cancer (TNBC) occurs in about 20% of all breast carcinomas. Because only a fraction of TNBCs responding to immune checkpoint blockade show a pre-existing T cell-inflamed tumor microenvironment (TME), it is critical to understand the mechanisms of T-cell exclusion. Tumor-cell intrinsic activation of the WNT/β–catenin pathway, overexpressed in 30% of human breast cancers, is linked to a T-cell excluded TME. In β–cateninhigh TNBC, however, the quality of the myeloid compartment has not been evaluated. Methods: A total of seventy-five, early-stage, untreated, TNBC patients was assessed (patient cohorts approved by IRB). β–catenin expression was detected by IHC and scored as high, intermediate, and low. The presence of T cells, tumor-associated macrophages (TAMs) and LAMP-expressing dendritic cells (LAMP+ DCs) was assessed by IHC using aCD3, aCD68, aCD163, and aLAMP, respectively. Public TNBC datasets TCGA (N = 157) and METABRIC (N = 319) were interrogated for correlations between β–catenin- and immune-associated genes. Results: Three patient groups (N = 25/group) were identified according to the negative, medium and high intracellular expression of β–catenin. As opposed to β–cateninlow TNBC, the β–cateninhigh group displayed significantly lower CD3+ T cells (median 5% ±7.37 SD vs median 30% ± 18.28 SD, p < 0.0001) and LAMP+ DCs (median 1% ± 2.515 SD vs median 10% ± 7.038 SD, p < 0.0001). The β–cateninlow group was enriched in lymphocyte-predominant TNBC. For the first time, we show that the immune-suppressive, CD68+CD163+ TAMs were strongly accumulated in the β–cateninhigh group (median 20% ± 12.20 SD vs median 5% ± 6.831 SD, p < 0.0001). The interrogation of the public TNBC datasets TCGA and METABRIC confirmed that – after patient statification according to the expression level of a WNT/β–catenin gene-signature (i.e. MMP7, SFRP1, WNT10A, WNT16, WNT9B) – multiple TAM-associated genes – identified by our group in a single-cell RNAseq dataset – were strongly upregulated in WNT/β–cateninhigh signature, highlighting the role of the WNT/β–catenin signaling pathway not only in T-cell exclusion but also in selective TAM accumulation. Conclusions: Immune-suppressive TAMs are accumulated in β–cateninhigh, T-cell excluded TNBCs emphasizing the importance of tumor-intrinsic factors in shaping the quality of the immune infiltrate.

scholarly journals Infiltration of CD8+ T cells into tumor cell clusters in triple-negative breast cancer

2019 ◽  
Vol 116 (9) ◽  
pp. 3678-3687 ◽  
Author(s):  
Xuefei Li ◽  
Tina Gruosso ◽  
Dongmei Zuo ◽  
Atilla Omeroglu ◽  
Sarkis Meterissian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cell ◽  
Cell Density ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Spatial Profile ◽  
Cell Clusters

Infiltration of CD8+ T lymphocytes into solid tumors is associated with good prognosis in various types of cancer, including triple-negative breast cancer (TNBC). However, the mechanisms underlying different infiltration levels are largely unknown. Here, we have characterized the spatial profile of CD8+ T cells around tumor cell clusters (tightly connected tumor cells) in the core and margin regions in TNBC patient samples. We found that in some patients, the CD8+ T cell density first decreases when moving in from the boundary of the tumor cell clusters and then rises again when approaching the center. To explain various infiltration profiles, we modeled the dynamics of T cell density via partial differential equations. We spatially modulated the diffusion/chemotactic coefficients of T cells (to mimic physical barriers) or introduced the localized secretion of a diffusing T cell chemorepellent. Combining the spatial-profile analysis and the modeling led to support for the second idea; i.e., there exists a possible chemorepellent inside tumor cell clusters, which prevents CD8+ T cells from infiltrating into tumor cell clusters. This conclusion was consistent with an investigation into the properties of collagen fibers which suggested that variations in desmoplastic elements does not limit infiltration of CD8+ T lymphocytes, as we did not observe significant correlations between the level of T cell infiltration and fiber properties. Our work provides evidence that CD8+ T cells can cross typical fibrotic barriers and thus their infiltration into tumor clusters is governed by other mechanisms possibly involving a local repellent.

scholarly journals 94 Effects of chemoimmunotherapy on the peripheral blood: insights from immune monitoring of a phase Ib trial of pembrolizumab and paclitaxel or capecitabine for triple-negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A103-A103
Author(s):  
Brie Chun ◽  
Joanna Pucilowska ◽  
Shu Ching Chang ◽  
Isaac Kim ◽  
Benjamin Nikitin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Peripheral Blood ◽  
Triple Negative ◽  
Early Stage ◽  
Medical Center ◽  
T Cell Subsets

BackgroundPembrolizumab plus curative-intent dose-dense anthracycline-based chemotherapy (ddAC) is associated with improved outcome in PD-L1-negative TNBC,1 whereas in the metastatic setting, clinical benefit of chemoimmunotherapy (taxane or gemcitabine/carboplatin) is restricted to PD-L1-positive patients.2 We hypothesize that this discordance could be related to immunomodulatory differences of the various chemotherapies. On-treatment serial monitoring of peripheral blood and tumoral T cells can be used to compare the effects of various regimens. We also hypothesize that T cell clonal expansion may differ across the regimens, and that tumor-enriched T cell clones are more likely to be tumor-reactive and expand following chemoimmunotherapy.MethodsBlood and tumor samples were collected from patients enrolled in a phase Ib clinical trial of palliative pembrolizumab and paclitaxel or capecitabine for metastatic TNBC, and from a contemporaneous cohort of patients treated with ddAC. T-cells were characterized using fresh whole blood flow cytometry and T-cell receptor (TCR) immunosequencing (immunoSEQ, Adaptive Biotechnologies) of DNA digests. Longitudinal regression was used to test the hypothesis that tumor-enriched T-cell clonotypes are more likely to expand in peripheral blood following therapy.ResultsWhen combined with pembrolizumab, paclitaxel versus capecitabine had similar effects on T-cells, resulting in a time-dependent lymphodepletion across all major T cell subsets (average CD3+ T cell fold-change capecitabine: -0.42, paclitaxel: -0.56, p = 0.80 t-test), whereas ddAC was associated with more profound lymphodepletion (CD3+ average fold-change: -1.21). Notably, ddAC was associated with higher odds of novel clonotype detection compared to capecitabine (odds ratio (OR): 3.42, 95% CI: 3.34–3.5) as well as compared to paclitaxel (OR: 1.53, 95% CI: 1.47–1.60). Significant expansion of tumoral clonotypes occurred in five patients receiving chemoimmunotherapy (average 4.2 unique clonotypes per patient, range 2–11). These clonotypes did not significantly expand over time in the blood. Similarly, T-cell clonotypes that were enriched within tumor did not exhibit measurable differences in serial trend within the peripheral blood.ConclusionsEffects to T cell subsets and clonotypes are similar between capecitabine and paclitaxel when combined with pembrolizumab. ddAC was more profoundly lymphotoxic, but resulted in greater clonotype expansion. These findings offer mechanistic insight onto the differences in clinical activity observed with chemoimmunotherapy in early stage versus metastatic TNBC. We observed no strong association between tumor clonotype enrichment and peripheral clonotype expansion, highlighting the unmet need to develop methods of monitoring tumor-reactive T cell clones in the context of immunotherapy.AcknowledgementsThe authors would like to acknowledge collaborators at the Earle A. Chiles Research Institute and Adaptive Biotechnologies for mentorship and guidance. Support for the clinical trial (NCT02734290), which comprised the metastatic cohort was provided by Merck and the Providence Opportunity Fund. Laboratory services were provided at no cost by Adaptive BiotechnologiesTrial RegistrationNCT02734290ReferencesSchmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020 Feb 27;382(9):810–821. doi: 10.1056/NEJMoa1910549.Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396(10265):1817–1828. doi:10.1016/S0140-6736(20)32531-9Ethics ApprovalAll patients provided written, informed consent. The study protocols for the collection of specimens from the early-stage breast cancer cohort and from the metastatic TNBC clinical trial were separately approved by independent review boards at Providence Portland Medical Center and Cedars Sinai Medical Center (mTNBC clinical trial only).

scholarly journals CD8 T Cell Score as a Prognostic Biomarker for Triple Negative Breast Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6968 ◽  
Author(s):  
Masanori Oshi ◽  
Mariko Asaoka ◽  
Yoshihisa Tokumaru ◽  
Li Yan ◽  
Ryusei Matsuyama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
Breast Cancer Patients

CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC and various GEO cohorts. The CD8 score correlated strongly with expression of CD8 genes. The score was highest for triple-negative breast cancer (TNBC), and a high score was associated with high tumor immune cytolytic activity and better survival in TNBC but not other breast cancer subtypes. In TNBC, tumors with a high CD8 score had enriched expression of interferon (IFN)-α and IFN-γ response and allograft rejection gene sets, and greater infiltration of anti-cancerous immune cells. The score strongly correlated with CD4 memory T cells in TNBC, and tumors with both a high CD8 score and high CD4 memory T cell abundance had significantly better survival. Finally, a high CD8 score was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, a high CD8 T cell score is associated with better survival in TNBC, particularly when tumor CD4 memory T cells were elevated. Our findings also suggest a possible use of the score as a predictive biomarker for response to immune checkpoint therapy.

scholarly journals Identification of an immune-suppressed subtype of feline triple-negative basal-like invasive mammary carcinomas, spontaneous models of breast cancer

Tumor Biology ◽  
2020 ◽  
Vol 42 (1) ◽  
pp. 101042831990105 ◽  
Author(s):  
Elie Dagher ◽  
Laura Simbault ◽  
Jérôme Abadie ◽  
Delphine Loussouarn ◽  
Mario Campone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Mammary Carcinomas ◽  
Epidermal Growth

Feline invasive mammary carcinomas are characterized by their high clinical aggressiveness, rare expression of hormone receptors, and pathological resemblance to human breast cancer, especially triple-negative breast cancer (negative to estrogen receptor, progesterone receptor, and epidermal growth factor receptor type 2). Recent gene expression studies of triple-negative breast cancers have highlighted their heterogeneity and the importance of immune responses in their biology and prognostic assessment. Indeed, regulatory T cells may play a crucial role in producing an immune-suppressed microenvironment, notably in triple-negative breast cancers. Feline invasive mammary carcinomas arise spontaneously in immune-competent animals, in which we hypothesized that the immune tumor microenvironment also plays a role. The aims of this study were to determine the quantity and prognostic value of forkhead box protein P3-positive peritumoral and intratumoral regulatory T cells in feline invasive mammary carcinomas, and to identify an immune-suppressed subgroup of triple-negative basal-like feline invasive mammary carcinomas. One hundred and eighty female cats with feline invasive mammary carcinomas, treated by surgery only, with 2-year follow-up post-mastectomy, were included in this study. Forkhead box protein P3, estrogen receptor, progesterone receptor, Ki-67, epidermal growth factor receptor type 2, and cytokeratin 14 expression were assessed by automated immunohistochemistry. Peritumoral regulatory T cells were over 300 times more abundant than intratumoral regulatory T cells in feline invasive mammary carcinomas. Peritumoral and intratumoral regulatory T cells were associated with shorter disease-free interval and overall survival in both triple-negative (ER–, PR–, HER2–, N = 123 out of 180) and luminal (ER+ and/or PR+, N = 57) feline invasive mammary carcinomas. In feline triple-negative basal-like (CK14+) mammary carcinomas, a regulatory T-cell–enriched subgroup was associated with significantly poorer disease-free interval, overall survival, and cancer-specific survival than regulatory T-cell-poor triple-negative basal-like feline invasive mammary carcinomas. High regulatory T-cell numbers had strong and negative prognostic value in feline invasive mammary carcinomas, especially in the triple-negative basal-like subgroup, which might contain a “basal-like immune-suppressed” subtype, as described in triple-negative breast cancer. Cats with feline invasive mammary carcinomas may thus be interesting spontaneous animal models to investigate new strategies of cancer immunotherapy in an immune-suppressed tumor microenvironment.

scholarly journals Clinicopathological Correlates of γδ T Cell Infiltration in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 765
Author(s):  
Florence Boissière-Michot ◽  
Ghita Chabab ◽  
Caroline Mollevi ◽  
Séverine Guiu ◽  
Evelyne Lopez-Crapez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Γδ T Cells ◽  
Cell Infiltration ◽  
Prognostic Impact ◽  
Γδ T Cell ◽  
T Cell Infiltration

The prognostic impact of the different tumor-infiltrating lymphocyte (TIL) subpopulations in solid cancers is still debated. Here, we investigated the clinicopathological correlates and prognostic impact of TILs, particularly of γδ T cells, in 162 patients with triple-negative breast cancer (TNBC). A high γδ T cell density (>6.625 γδ T cells/mm2) was associated with younger age (p = 0.008), higher tumor histological grade (p = 0.002), adjuvant chemotherapy (p = 0.010), BRCA1 promoter methylation (p = 0.010), TIL density (p < 0.001), and PD-L1 (p < 0.001) and PD-1 expression (p = 0.040). In multivariate analyses, γδ T cell infiltration (cutoff = 6.625 γδ T cells/mm2) was an independent prognostic factor (5-year relapse-free survival: 63.3% vs. 89.8%, p = 0.027; 5-year overall survival: 73.8% vs. 89.9%, p = 0.031, for low vs. high infiltration). This prognostic impact varied according to the tumor PIK3CA mutational status. High γδ T cell infiltration was associated with better survival in patients with PIK3CA wild-type tumors, but the difference was not significant in the subgroup with PIK3CA-mutated tumors. Altogether, these data suggest that high γδ T cell infiltrate is correlated with immune infiltration and might represent a candidate prognostic tool in patients with TNBC.

scholarly journals Interleukin-17-based cytokine signaling as a determinant for tumor immune microenvironment with prognostic value in triple-negative breast cancer

2021 ◽  
Author(s):  
Victor C. Kok ◽  
Charles C.N. Wang ◽  
Szu-Han Liao ◽  
De-Lun Chen
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Nk Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Receptor Interaction ◽  
Cytokine Signaling ◽  
Interleukin 17

Abstract Background: Only a proportion of triple-negative breast cancer (TNBC) is immunotherapy-responsive. We hypothesized that the tumor microenvironment (TME) might influence the outcomes of TNBC and investigated the relevant signaling pathways. Methods: RNA-seq data of 115 TNBC samples and 112 normal adjacent tissues were retrieved for ESTIMATE, CIBERSORTx, X2K, KEGG, and GSVA analyses. The immune score (IS) and stromal score (SS) were calculated and correlated with the overall survival (OS) in TNBC. Finally, we validated the altered transcription factor (TF) genes in the cBioPortal. Results: The SS is a good predictor of the OS (better survival in SS-low patients; P = 0.0081). In line with these results, when compared with IS-low/SS-high patients, IS-high/SS-low patients showed a better OS (P = 0.045). Moreover, macrophages were polarized toward the M2 phenotypes in IS-low/SS-high patients (P < 0.001). Compared with IS-low/SS-high patients, CIBERSORTx also showed that IS-high/SS-low patients had an increased number of memory B cells, CD8+ T cells (14.8% vs. 3.7%, p = 0.0286), activated CD4+ memory T cells, follicular helper T cells, and activated NK cells in the TME; additionally, fewer resting NK cells were detected in the TME (P = 0.0108). Additionally, there were 284 upregulated and 367 downregulated DEGs (Differentially Expressed Genes) in IS-high/SS-low, and 187 upregulated and 183 downregulated DEGs in IS-low/SS-high patients. KEGG analysis further revealed that the DEGs were enriched in the IL-17 and cytokine-cytokine receptor interaction pathways. Of note, as per the cBioPortal platform, we discovered that 13% of ER-negative, HER2-unamplified BC patients harbored IL17RA deep deletions and 25% harbored TRAF3IP2 amplifications; interestingly, the nine altered TF genes were associated with significantly worse relapse-free survival and OS, in the context of 2,377 and 4,819 BC patients, respectively.Conclusions: The TME with different immune cell components influences the survival of TNBC patients. IS-high/SS-low patients show a better overall survival. Further studies are required to examine whether an immune/stromal state also predicts the response to immunotherapy.

Sign in / Sign up

Export Citation Format

Share Document