Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy

Friedrich, Michael W.; Jasinski‐Bergner, Simon; Lazaridou, Maria-Filothei; Subbarayan, Karthikeyan; Massa, Chiara; Tretbar, Sandy; Müeller, Anja; Handke, Diana; Biehl, Katharina; Bukur, Jürgen; Donia, Marco; Mandelboim, Ofer; Seliger, Barbara

doi:10.1007/s00262-019-02373-1

Cited by 59 publications

(61 citation statements)

References 146 publications

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“…The most important mechanism of immune evasion by tumors is the inhibition of anti-tumor immune responses. 40 Tumor-induced immunosuppression inhibits T cell infiltration. However, some checkpoint molecules on tumor cells, APCs, or T cells might be involved in inhibiting the activation of tumorspecific T cells.…”

Section: Discussionmentioning

confidence: 99%

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Zhang

et al. 2020

OncoImmunology

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In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2 D4) was found to enhance IFN-γ-producing-CD8 + T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2 D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2 D4 and antitumor immunity, as evidenced by the reversal of tumor-infiltrating CD8 + T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.

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Section: Discussionmentioning

confidence: 99%

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Zhang

et al. 2020

OncoImmunology

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“…In addition, sHLA-G levels were higher in the first trimester of pregnancy compared to the second and third trimesters (19), while low levels of sHLA-G have been detected in recurrent miscarriage (20), miscarriage in IVF pregnancies (21), as well as preeclampsia (22). In addition, HLA-G as an important mediator of immune escape has been also described in other immunemediated disorders, malignancies, and transplantation (23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer

Nowak

Wilczyńska

Radwan³

et al. 2020

Front. Immunol.

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“…Additionally, miR-9, which functions as a tumor suppressor in NPC [55], positively regulated the expression of MHC class I genes (such as HLA-B and HLA-F) in NPC [12]. The previous studies revealed that the non-classical HLA-F and HLA-G act as the important mediators of immune escape [56,57]. This study demonstrated that miR-19a or miR-19b-1 overexpression in cancer cells led to a general downward trend in the expression profile of MHC Class I molecules (such as HLA-B, HLA-E, HLA-F, HLA-G or HLA-J), which has never been reported in other physiological and pathological processes.…”

Section: Discussionmentioning

confidence: 99%

miR-19 regulates the expression of interferon-induced genes and MHC class I genes in human cancer cells

Lin

Chen

et al. 2020

Int. J. Med. Sci.

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MicroRNA -19 (miR-19) is identified as the key oncogenic component of the miR-17-92 cluster. When we explored the functions of the dysregulated miR-19 in lung cancer, microarray-based data unexpectedly demonstrated that some immune and inflammatory response genes (i.e., IL32, IFI6 and IFIT1) were generally down-regulated by miR-19 overexpression in A549 cells, which prompted us to fully investigate whether the miR-19 family (i.e., miR-19a and miR-19b-1) was implicated in regulating the expression of immune and inflammatory response genes in cancer cells. In the present study, we observed that miR-19a or miR-19b-1 overexpression by miRNA mimics in the A549, HCC827 and CNE2 cells significantly downregulated the expression of interferon (IFN)-regulated genes (i.e., IRF7, IFI6, IFIT1, IFITM1, IFI27 and IFI44L). Furthermore, the ectopic miR-19a or miR-19b-1 expression in the A549, HCC827, CNE2 and HONE1 cells led to a general downward trend in the expression profile of major histocompatibility complex (MHC) class I genes (such as HLA-B, HLA-E, HLA-F or HLA-G); conversely, miR-19a or miR-19b-1 inhibition by the miRNA inhibitor upregulated the aforementioned MHC Class I gene expression, suggesting that miR-19a or miR-19b-1 negatively modulates MHC Class I gene expression. The miR-19a or miR-19b-1 mimics reduced the expression of interleukin (IL)-related genes (i.e., IL1B, IL11RA and IL6) in the A549, HCC827, CNE2 or HONE1 cells. The ectopic expression of miR-19a or miR-19b-1 downregulated IL32 expression in the A549 and HCC827 cells and upregulated IL32 expression in CNE2 and HONE1 cells. In addition, enforced miR-19a or miR-19b-1 expression suppressed IL-6 production by lung cancer and nasopharyngeal carcinoma (NPC) cells. Taken together, these findings demonstrate, for the first time, that miR-19 can modulate the expression of IFN-induced genes and MHC class I genes in human cancer cells, suggesting a novel role of miR-19 in linking inflammation and cancer, which remains to be fully characterized.

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Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy

Cited by 59 publications

References 146 publications

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models

Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer

miR-19 regulates the expression of interferon-induced genes and MHC class I genes in human cancer cells

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