Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer

Jeong, Seri; Lee, Nuri; Park, Min-Jeong; Jeon, Kibum; Song, Wonkeun

doi:10.3390/cancers13205225

Cited by 10 publications

(10 citation statements)

References 116 publications

(163 reference statements)

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“…Currently, there are diverse developed PD-L1 assays to evaluate PD-L1 expression: SP142, SP263, 28-82, 22C3, E1L3N, 73-10, E1J2J, 5H1, 4059 and 9A11, among others [ 6 , 22 , 26 , 27 , 28 ]. The IHC assays that are most frequently used to determine the expression level of PD-L1 are PD-L1 IHC 22C3pharmDx Assay (PD-L1 22C3, DAKO) and SP142 Assay (PD-L1 SP142, VENTANA) ( Table 2 ) [ 3 , 5 , 6 , 28 , 29 ]. Normally, the approval of immunotherapy drugs is often linked to a certain PD-L1 IHC assay.…”

Section: Resultsmentioning

confidence: 99%

“…The PD-L1 immunohistochemistry (IHC) biomarker landscape is complex due to the heterogeneity of IHC assays, with diverse scoring algorithms approved for different scenarios and tumor indications [ 3 ]. Currently, the most commonly used anti-PD-L1 antibody clones are 22C3, SP142, SP263, 28-8, E1L3N and 73-10 [ 4 , 5 , 6 ]. Insufficient studies have evaluated the PD-L1 expression in tumor and immune cells in BC, and preliminary data are divergent with still great variability in the analysis.…”

Section: Introductionmentioning

confidence: 99%

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Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

Abad

Calabuig

Mena

et al. 2022

Cancers

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Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

Abad

Calabuig

Mena

et al. 2022

Cancers

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“…In determining the impact of pro-inflammatory cytokines on the expression of PD-L1 and PD-L2 in TNBC cells, we have analyzed the effects of TNFα, IL-1β and IFNγ, each alone and in all possible combinations, in pairs and as a triplet stimulation (cytokine concentrations were selected as described in Section 2 ). Moreover, in view of the fact that both PD-L1 and PD-L2 were found to be expressed by breast tumor cells in patients and to be associated with each other [ 50 , 51 , 52 , 53 , 77 ], we have also analyzed the proportions of TNBC cells that co-expressed PD-L1 and PD-L2 together.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, we have investigated the impact of the pro-inflammatory cytokines on PD-L2 expression by the cancer cells. Emerging findings have recently demonstrated that PD-L2, the other PD-1 ligand, is expressed by cancer cells and is connected to poor prognosis, including in breast cancer, presumably by its ability to down-regulate immune activities [ 50 , 51 , 52 , 53 , 54 ].…”

Section: Introductionmentioning

confidence: 99%

Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

Baram

Oren

Erlichman

et al. 2022

Cancers

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Pro-inflammatory cytokines play key roles in elevating cancer progression in triple-negative breast cancer (TNBC). We demonstrate that specific combinations between TNFα, IL-1β and IFNγ up-regulfated the proportion of human TNBC cells co-expressing the inhibitory immune checkpoints PD-L1 and PD-L2: TNFα + IL-1β in MDA-MB-231 cells and IFNγ + IL-1β in BT-549 cells; in the latter cells, the process depended entirely on STAT1 activation, with no involvement of p65 (CRISPR-Cas9 experiments). Highly significant associations between the pro-inflammatory cytokines and PD-L1/PD-L2 expression were revealed in the TCGA dataset of basal-like breast cancer patients. In parallel, we found that the pro-inflammatory cytokines regulated the expression of the soluble receptors of tumor necrosis factor α (TNFα), namely sTNFR1 and sTNFR2; moreover, we revealed that sTNFR1 and sTNFR2 serve as anti-metastatic and protective factors in TNBC, reducing the TNFα-induced production of inflammatory pro-metastatic chemokines (CXCL8, CXCL1, CCL5) by TNBC cells. Importantly, we found that in the context of inflammatory stimulation and also without exposure to pro-inflammatory cytokines, elevated levels of PD-L1 have down-regulated the production of anti-tumor sTNFR1 and sTNFR2. These findings suggest that in addition to its immune-suppressive activities, PD-L1 may promote disease course in TNBC by inhibiting the protective effects of sTNFR1 and sTNFR2.

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“…However, there is no standardized method for PD-L1 assessment. SP142, SP263, 28-82, 22C3, E1L3N, 73–10, E1J2J, 5H1, 4059, and 9A11 are some assays among others [ 43 ]; of these, the PD-L1 IHC 22C3pharmDx Assay (PD-L1 22C3, DAKO) and SP142 Assay (PD-L1 SP142, VENTANA) are used most often [ 47 , 48 , 49 , 50 ]. Commonly, the approval of immunotherapy drugs joins with a predetermined IHC assay.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy

Nicolini

Carpi

2022

Biomedicines

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Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusion: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed.

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Currently Used Laboratory Methodologies for Assays Detecting PD-1, PD-L1, PD-L2 and Soluble PD-L1 in Patients with Metastatic Breast Cancer

Cited by 10 publications

References 116 publications

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

Immune Checkpoint Inhibitors and Other Immune Therapies in Breast Cancer: A New Paradigm for Prolonged Adjuvant Immunotherapy

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