Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer

Yamashita, Kohei; Iwatsuki, Masaaki; Yasuda-Yoshihara, Noriko; Morinaga, Takeshi; Nakao, Yosuke; Harada, Kazuto; Eto, Kojiro; Kurashige, Junji; Hiyoshi, Yukiharu; Ishimoto, Takatsugu; Nagai, Yoshinori; Iwagami, Shiro; Baba, Yoshifumi; Miyamoto, Yuji; Yoshida, Naoya; Ajani, Jaffer A.; Baba, Hideo

doi:10.1038/s41416-020-01138-3

Cited by 34 publications

(14 citation statements)

References 30 publications

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“…PD-1 is an immune checkpoint molecule that is expressed on several types of immune cells, including effector T cells. It induces exhaustion of the effector function by engaging its ligand PD-L1 [ 30 ]. Several studies have reported the status of PD-1 or PD-L1 in gastric cancer, and PD-1 or PD-L1 has been shown to be potential predictive biomarker for recurrence and prognosis for gastric cancer in certain settings [ 31 – 33 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells

Zhai

Shen

et al. 2022

Cancer Immunol Immunother

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Background The pretherapeutic serum interleukin-8 (sIL-8) levels have been revealed to be increased in about half of patients with locally advanced gastric cancer. However, the roles of IL-8 in lymph node metastasis (LNM) and the underlying mechanisms remain unclear. Methods 146 patients with primary gastric carcinoma were enrolled in this study. ELISA was used to measure IL-8 levels. The CD4/CD8 ratio and programmed cell death-1 (PD-1) expression of T cells in primary tumor tissues, tumor-draining lymph nodes (TDLNs) and non-draining lymph nodes (NDLNs) were assayed with flow cytometry. Protein expression of the molecules was determined with immunohistochemistry, western blotting or immunoprecipitation. The gastric cancer mouse tumor model with LNM was utilized to determine the role of IL-8 in regulation of tumor metastasis and progression. Results The elevated sIL-8 levels were associated with LNM and poor prognosis in gastric cancer. Furthermore, sIL-8 was identified to be prominently produced by gastric cancer-associated fibroblasts (CAFs). Elevated IL-8 can up-regulate PD-1 expression in CD8+ T cells, resulting in immunosuppression in primary tumors and TDLNs, which enhances LNM of gastric cancer. Molecularly, IL-8 increases PD-1 expression through JAK2/STAT3 signaling activation, and inhibits its ubiquitination via Fbxo38 down-regulation. In addition, the in vivo studies in mouse gastric cancer model demonstrated that IL-8 promotes LNM via PD-1 up-regulation in CD8+ T cells. Conclusion The present study elucidates the pro-metastatic role of elevated IL-8 in gastric cancer, and provides novel insights to enhance immune checkpoint blockade therapy for anti-PD-1 in gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells

Zhai

Shen

et al. 2022

Cancer Immunol Immunother

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“…PD-L1 suppresses immune effectors through the ligation of PD-1 [ 208 ]. Both NK cells and T cells are important sources of IFN-γ that could stimulate tumor PD-L1 expression [ 209 ]. However, whether PD-L1 has a major role is suppressing trastuzumab-induced immunity and clinical activity is not clear from clinic studies.…”

Section: Molecular and Cellular Mechanisms Of Resistance To Trastuzumabmentioning

confidence: 99%

Resistance to Trastuzumab

Vivekanandhan

Knutson

2022

Cancers

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One of the most impactful biologics for the treatment of breast cancer is the humanized monoclonal antibody, trastuzumab, which specifically recognizes the HER2/neu (HER2) protein encoded by the ERBB2 gene. Useful for both advanced and early breast cancers, trastuzumab has multiple mechanisms of action. Classical mechanisms attributed to trastuzumab action include cell cycle arrest, induction of apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). Recent studies have identified the role of the adaptive immune system in the clinical actions of trastuzumab. Despite the multiple mechanisms of action, many patients demonstrate resistance, primary or adaptive. Newly identified molecular and cellular mechanisms of trastuzumab resistance include induction of immune suppression, vascular mimicry, generation of breast cancer stem cells, deregulation of long non-coding RNAs, and metabolic escape. These newly identified mechanisms of resistance are discussed in detail in this review, particularly considering how they may lead to the development of well-rationalized, patient-tailored combinations that improve patient survival.

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“…Trastuzumab’s capacity in upregulating PD-L1 expression, by the recruitment of IFNgamma-secreting immune effector cells, has been shown as a mechanism of resistance to trastuzumab [ 63 ]. Furthermore, the mAbs that are bound to tumor cells engage innate immune effector cells via their Fc receptor, resulting in ADCC [ 64 , 65 ], which in turn also results in the upregulation of PD-L1 [ 66 ]. It has been shown that the increased ability of tumor cells to evade the immune system is attributed to their PD-L1 expression capacity, allowing their interaction with PD-1-expressing immune cells [ 67 ].…”

Section: Combination Of Her-2/neu-targeted Therapy With Immune Checkp...mentioning

confidence: 99%

Combined Vaccination with B Cell Peptides Targeting Her-2/neu and Immune Checkpoints as Emerging Treatment Option in Cancer

Tobias

Drinić

Schmid

et al. 2022

Cancers

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The application of monoclonal antibodies (mAbs), targeting tumor-associated (TAAs) or tumor-specific antigens or immune checkpoints (ICs), has shown tremendous success in cancer therapy. However, the application of mAbs suffers from a series of limitations, including the necessity of frequent administration, the limited duration of clinical response and the emergence of frequently pronounced immune-related adverse events. However, the introduction of mAbs has also resulted in a multitude of novel developments for the treatment of cancers, including vaccinations against various tumor cell-associated epitopes. Here, we reviewed recent clinical trials involving combination therapies with mAbs targeting the PD-1/PD-L1 axis and Her-2/neu, which was chosen as a paradigm for a clinically highly relevant TAA. Our recent findings from murine immunizations against the PD-1 pathway and Her-2/neu with peptides representing the mimotopes/B cell peptides of therapeutic antibodies targeting these molecules are an important focus of the present review. Moreover, concerns regarding the safety of vaccination approaches targeting PD-1, in the context of the continuing immune response, as a result of induced immunological memory, are also addressed. Hence, we describe a new frontier of cancer treatment by active immunization using combined mimotopes/B cell peptides aimed at various targets relevant to cancer biology.

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Trastuzumab upregulates programmed death ligand-1 expression through interaction with NK cells in gastric cancer

Cited by 34 publications

References 30 publications

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells

Resistance to Trastuzumab

Combined Vaccination with B Cell Peptides Targeting Her-2/neu and Immune Checkpoints as Emerging Treatment Option in Cancer

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