Immune checkpoint inhibitors for triple-negative breast cancer: From immunological mechanisms to clinical evidence

Farshbafnadi, Melina; Khoshbin, Amin Pastaki; Rezaei, Nima

doi:10.1016/j.intimp.2021.107876

Cited by 19 publications

(15 citation statements)

References 98 publications

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“…Immunotherapies that use antibodies directed to inhibitory immune checkpoints—such as PD-L1, PD-1 and CTLA-4—have introduced a major breakthrough in cancer therapy, with relatively good impact on disease course, primarily in melanoma [ 6 , 7 ]. In breast cancer, it was suggested that treatment by immune checkpoint blockades (ICBs) may apply particularly to TNBC tumors because of their relatively high mutation rate, which is expected to generate neo-antigens [ 8 , 9 , 10 , 11 ]. Studies of inhibitory immune checkpoints in TNBC have addressed mainly the PD-L1/PD-1 axis; they demonstrated the expression of PD-L1 and PD-1 by cancer cells and immune cells in the tumor and analyzed their connection to patient survival.…”

Section: Introductionmentioning

confidence: 99%

“…However, PD-L1 expression was, at times, associated with improved survival, primarily when high levels of tumor-infiltrating lymphocytes, which, by themselves, are connected to better prognosis in TNBC, were present in the tumors. This observation is presumed to reflect stronger immune activation and the dynamic nature of immune activities at the tumor site [ 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Overall, the different clinical trials that targeted the PD-L1/PD-1 axis demonstrated a relatively low-to-moderate improvement in objective response rates in TNBC patients; in most cases, effectiveness was increased by chemotherapies, possibly due to the exposure of neo-antigens, leading to increased activation of anti-tumor immune responses [ 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The relatively limited efficacy of ICBs in TNBC patients calls for identification of the mechanisms leading to poor impact of immunotherapies in this disease subtype.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Erlichman

Baram

Meshel

et al. 2022

Cancers

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Therapies targeting the PD-L1/PD-1 axis have recently been introduced to triple-negative breast cancer (TNBC) with limited efficacy, suggesting that this axis promotes tumor progression through mechanisms other than immune suppression. Here, we over-expressed WT-PD-L1 in human TNBC cells (express endogenous PD-L1) and in luminal-A breast cancer cells (no endogenous PD-L1 expression) and demonstrated that cell-autonomous PD-L1 activities lead to increased tumor cell growth, invasion and release of pro-metastatic factors (CXCL8, sICAM-1, GM-CSF). These activities were promoted by PD-1 and were inhibited by mutating S283 in PD-L1. Invasion of WT-PD-L1-cells required signaling by chemokine receptors CXCR1/2, CCR2 and CCR5 through autocrine circuits involving CXCL8, CCL2 and CCL5. Studies with T cell-deficient mice demonstrated that cell-autonomous WT-PD-L1 activities in TNBC cells increased tumor growth and metastasis compared to knock-out (KO)-PD-L1-cells, whereas S283A-PD-L1-expressing cells had minimal ability to form tumors and did not metastasize. Overall, our findings reveal autonomous and PD-1-induced tumor-promoting activities of PD-L1 that depend on S283 and on chemokine circuits. These results suggest that TNBC patients whose tumors express PD-L1 could benefit from therapies that prevent immune suppression by targeting PD-1/CTLA-4, alongside with antibodies to PD-L1, which would allow maximal impact by mainly targeting the cancer cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Erlichman

Baram

Meshel

et al. 2022

Cancers

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“…Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that can suppress the inhibitory pathway such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and the PD-1/PD-L1 axis [128]. ICIs can reverse immune suppression by binding to either the immune checkpoint molecule such as cytotoxic CTLA-4 and PD-1 or the immune checkpoint ligand such as PD-L1 [129].…”

Section: Checkpoint Inhibitors Deliverymentioning

confidence: 99%

Black Phosphorus, an Emerging Versatile Nanoplatform for Cancer Immunotherapy

et al. 2021

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Black phosphorus (BP) is one of the emerging versatile nanomaterials with outstanding biocompatibility and biodegradability, exhibiting great potential as a promising inorganic nanomaterial in the biomedical field. BP nanomaterials possess excellent ability for valid bio-conjugation and molecular loading in anticancer therapy. Generally, BP nanomaterials can be classified into BP nanosheets (BPNSs) and BP quantum dots (BPQDs), both of which can be synthesized through various preparation routes. In addition, BP nanomaterials can be applied as photothermal agents (PTA) for the photothermal therapy (PTT) due to their high photothermal conversion efficiency and larger extinction coefficients. The generated local hyperpyrexia leads to thermal elimination of tumor. Besides, BP nanomaterials are capable of producing singlet oxygen, which enable its application as a photosensitizer for photodynamic therapy (PDT). Moreover, BP nanomaterials can be oxidized and degraded to nontoxic phosphonates and phosphate under physiological conditions, improving their safety as a nano drug carrier in cancer therapy. Recently, it has been reported that BP-based PTT is capable of activating immune responses and alleviating the immunosuppressive tumor microenvironment by detection of T lymphocytes and various immunocytokines, indicating that BP-based nanocomposites not only serve as effective PTAs to ablate large solid tumors but also function as an immunomodulation agent to eliminate discrete tumorlets. Therefore, BP-mediated immunotherapy would provide more possibilities for synergistic cancer treatment.

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“…Due to the potential of the immune system in various new treatment strategies, immunotherapy has attracted the attention of researchers, including adoptive cell therapy, oncolytic virus and the most noteworthy immune checkpoint blockade therapy (5). Monoclonal antibodies against PD-1/PD-L1 and CTLA-4 have now entered clinical trials for the clinical treatment of triple negative breast cancer (6). Our recent study has showed that human leukocyte antigen-G (HLA-G) was a pivotal mediator of HER2 positive breast cancer resistance to trastuzumab and blockade of HLA-G can improve the antitumor activity of NK cells significantly (7).…”

Section: Introductionmentioning

confidence: 99%

Roles of HLA-G/KIR2DL4 in Breast Cancer Immune Microenvironment

2022

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Human leukocyte antigen (HLA)-G is a nonclassical MHC Class I molecule, which was initially reported as a mediator of immune tolerance when expressed in extravillous trophoblast cells at the maternal-fetal interface. HLA-G is the only known ligand of killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), an atypical family molecule that is widely expressed on the surface of NK cells. Unlike other KIR receptors, KIR2DL4 contains both an arginine–tyrosine activation motif in its transmembrane region and an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail, suggesting that KIR2DL4 may function as an activating or inhibitory receptor. The immunosuppressive microenvironment exemplified by a rewired cytokine network and upregulated immune checkpoint proteins is a hallmark of advanced and therapy-refractory tumors. Accumulating evidence has shown that HLA-G is an immune checkpoint molecule with specific relevance in cancer immune escape, although the role of HLA-G/KIR2DL4 in antitumor immunity is still uncharacterized. Our previous study had shown that HLA-G was a pivotal mediator of breast cancer resistance to trastuzumab, and blockade of the HLA-G/KIR2DL4 interaction can resensitize breast cancer to trastuzumab treatment. In this review, we aim to summarize and discuss the role of HLA-G/KIR2DL4 in the immune microenvironment of breast cancer. A better understanding of HLA-G is beneficial to identifying novel biomarker(s) for breast cancer, which is important for precision diagnosis and prognostic assessment. In addition, it is also necessary to unravel the mechanisms underlying HLA-G/KIR2DL4 regulation of the immune microenvironment in breast cancer, hopefully providing a rationale for combined HLA-G and immune checkpoints targeting for the effective treatment of breast cancer.

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Immune checkpoint inhibitors for triple-negative breast cancer: From immunological mechanisms to clinical evidence

Cited by 19 publications

References 98 publications

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Tumor Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Human Breast Cancer Are Mediated by PD-L1-S283 and Chemokine Axes

Black Phosphorus, an Emerging Versatile Nanoplatform for Cancer Immunotherapy

Roles of HLA-G/KIR2DL4 in Breast Cancer Immune Microenvironment

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