Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion

Chaganty, Bharat Kumar Reddy; Qiu, Songbo; Gest, Anneliese; Lü, Yang; Ivan, Cristina; Calin, George A.; Weiner, Louis M.; Fan, Zhen

doi:10.1016/j.canlet.2018.05.009

Cited by 147 publications

(100 citation statements)

References 65 publications

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“…Currently, atezolizumab is the only FDA-approved immune checkpoint inhibitor for BC (TNBC) treatment. Out of many new drugs that are under clinical trial, margetuximab (MGA-H22) received FDA approval for fast track investigation on its potency to treat HER2 + metastatic BC [146][147][148]. This is a novel HER2-targeted monoclonal antibody tailored to enhance the binding affinity to multiple sites by mediating activation of Fc-γ receptors.…”

Section: Pd-1/pd-l1 and Her2 Crosstalk In Breast Cancermentioning

confidence: 99%

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Padmanabhan

Kheraldine

Meskin

et al. 2020

Cancers

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Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2+) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2+ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2+ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2+ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2+ breast cancer and immune checkpoint inhibitors.

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Section: Pd-1/pd-l1 and Her2 Crosstalk In Breast Cancermentioning

confidence: 99%

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Padmanabhan

Kheraldine

Meskin

et al. 2020

Cancers

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“…Tumor‐infiltrating immune cells (TIICs) are essential components of the tumor microenvironment and can alter the immune status of the tumor. Several studies have demonstrated therapeutic strategies against tumors by targeting TIICs . Clinical outcomes and the potential mechanisms involving PCa and TIICs have been widely reported.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have demonstrated therapeutic strategies against tumors by targeting TIICs. [15][16][17][18][19] Clinical outcomes and the potential mechanisms involving PCa and TIICs have been widely reported. Kaur et al 20 marked the T cells in PCa tissues with CD3, CD8, and FOXP3 immunostaining and revealed that ERG activity and PTEN loss were affected by the high proportion of T cells, but clinical outcomes showed no association with these results.…”

mentioning

confidence: 99%

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

et al. 2019

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Prostate cancer (PCa), a severe health burden for males, accounts for the second frequent cancer and fifth tumor specific death cancer around the world. Several studies on tumor‐infiltrating immune cells (TIICs) have shown inconsistent and controversial results to PCa. We downloaded a gene expression matrix and clinical information from TCGA, and CIBERSORT was used to identify the proportion of TIICs. Wilcoxon's Sign Rank Test evaluated different gene expression levels in PCa and normal tissues. Kaplan‐Meier curves were used to evaluate the associations of TIICs and recurrence‐free survival (RFS). Finally, based on the preset P‐value of .05, the distribution of TIICs in 73 PCa tissues and 11 normal tissues was illustrated. Activated CD4 + T cells and M0 macrophages account for a high proportion in PCa tissues, while neutrophils and monocytes were found at a high density in normal tissues. Further results showed that the density of plasma cells, Treg cells and resting mast cells were associated with advanced PCa. Additionally, M2 macrophages affected the RFS of PCa patients, and AR was also involved. In the current study, we first evaluated the immune infiltration among PCa and revealed that M2 macrophages could predict the prognosis of PCa patients. Meanwhile, based on the LASSO regression analysis, we established a novel nomogram to assess the recurrence risk of PCa based on immune cell proportions and clinical features.

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“…Some of these phenomena could also be observed after treatment with trastuzumab. In breast cancer, increased tumor-infiltrating lymphocytes was associated with the efficacy of trastuzumab-based treatment, while PD-L1 was upregulated in tumor cells, which resisted trastuzumab [67,68]. Considering their bidirectional effect on anti-tumor immunity, immune checkpoint inhibitors may reverse the immunosuppressive effect of anti-ERBB antibodies by unleashing the function of effector T cells and impeding Tregs activation.…”

Section: Combination With Other Targeted Agentsmentioning

confidence: 99%

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects

Zhou

Zhang

2019

Front. Med.

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Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients' outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.

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Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion

Cited by 147 publications

References 65 publications

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects

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