The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC)

Tomioka, Nobumoto; Azuma, Manabu; Ikarashi, Mayuko; Yamamoto, Misazō; Sato, Mariko; Watanabe, Kenichi; Yamashiro, Katsushige; Takahashi, Masato

doi:10.1007/s12282-017-0781-0

Cited by 91 publications

(71 citation statements)

References 38 publications

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“…17,35 TNBC patients with high PD-L1 expression on tumor cells have extremely unfavorable outcomes after chemotherapy compared to patients with low PD-L1 expression. 40 Based on this data, it may imply that PD-L1 upregulation may lead to AF resistance in TNBCs. PD-L1 expression on cancer cells is increased by an increased tumor infiltration of CD8 +Ve T-cells as observed in hepatocellular carcinoma patients.…”

Section: Discussionmentioning

confidence: 78%

“…In recent years, upregulation of immune checkpoint PD‐L1 has emerged as a potential resistance mechanism to neoadjuvant chemotherapies and targeted therapies . TNBC patients with high PD‐L1 expression on tumor cells have extremely unfavorable outcomes after chemotherapy compared to patients with low PD‐L1 expression . Based on this data, it may imply that PD‐L1 upregulation may lead to AF resistance in TNBCs.…”

Section: Discussionmentioning

confidence: 94%

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Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 94%

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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“…Tomioka et al have shown that low TILs in combination with high PD-L1 expression predict an unfavorable prognosis. Within the abundant lymphocytic stroma in TNBC, PD-L1 could possibly operate as a target for therapeutic options [58]. Thus, in further research, in addition to a standardised estimation of TSR, the biology or quality of the stroma should be taken into account as well, in both general breast cancer and especially in TNBC patients in order to clarify the paradox and subsequently to lay a foundation regarding targeted therapy.…”

Section: Discussion Of Current Literaturementioning

confidence: 99%

The prognostic value of tumour–stroma ratio in primary breast cancer with special attention to triple-negative tumours: a review

Kramer

Vangangelt

Pelt

et al. 2018

Breast Cancer Res Treat

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Purpose There is a strong need to improve the prognostication of breast cancer patients in order to prevent over- and undertreatment, especially when considering adjuvant chemotherapy. Tumour stroma characteristics might be valuable in predicting disease progression. Methods Studies regarding the prognostic value of tumour–stroma ratio (TSR) in breast cancer are evaluated. Results A high stromal content is related to a relatively poor prognosis. The most pronounced prognostic effect of this parameter seems to be observed in the triple-negative breast cancer (TNBC) subtype. Conclusions TSR assessment might represent a simple, fast and reproducible prognostic factor at no extra costs, and could possibly be incorporated into routine pathological diagnostics. Despite these advantages, a robust clinical validation of this parameter has yet to be established in prospective studies. Electronic supplementary material The online version of this article (10.1007/s10549-018-4987-4) contains supplementary material, which is available to authorized users.

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“…Studies have shown that TILs are one of the favorable prognostic markers in triple-negative or HER2 + breast cancer patients, but not in those with ER + /HER2 − [53][54][55][56][57]. Tomioka and colleagues reported that unfavorable prognosis was observed in triple-negative breast cancer with low TILs and high PD-L1 [58]. Understanding the factor(s) stimulating TILs may help to design novel strategies in switching 'cold-' to 'hot-' tumors.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 mRNA expression modifies the effect of T cell activation score on patient survival in breast cancer

Lü

Huang

et al. 2019

BMC Cancer

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Background: Effector CD8 + T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer. Tumor suppressor BRCA1 and cell cycle regulator CCND1 play a critical role in maintaining genome integrity and tumorigenesis, respectively. However, it is still unclear how BRCA1 and CCND1 expression levels affect the effect of T cell activation on breast cancer patient survival. Methods: The interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients. Results: Among the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20-0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19-0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135). Conclusions: BRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.

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The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC)

Abstract: The patients with TNBCs with combined Low-TILs and High-PD-L1 status in pre-PST situation showed unfavorable prognosis. The subset of TNBCs with Low-TILs and High-PD-L1 status could be the therapeutic target for immune checkpoint inhibitor.

Cited by 91 publications

References 38 publications

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

The prognostic value of tumour–stroma ratio in primary breast cancer with special attention to triple-negative tumours: a review

BRCA1 mRNA expression modifies the effect of T cell activation score on patient survival in breast cancer

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