Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells

Brea, Elliott J.; Oh, Claire Y.; Manchado, Eusebio; Budhu, Sadna; Gejman, Ron S.; Mo, George; Mondello, Patrizia; Han, Jee Eun; Jarvis, Casey A.; Ulmert, David; Qiu, Xiang; Chang, Amy; Garippa, Ralph; Merghoub, Taha; Wolchok, Jedd D.; Rosen, Neal; Lowe, Scott W.; Scheinberg, David A.

doi:10.1158/2326-6066.cir-16-0177

Cited by 143 publications

(134 citation statements)

References 49 publications

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“…Most of the studies have shown that MEK inhibition can increase the expression of intrinsic and IFN-γ-induced HLA/ MHC I/II in cancer cell lines, including melanoma, mesothelioma, prostate, gastric, and esophageal cancer cell lines [103][104][105]. Similarly to BRAF inhibition, treatment of mutant melanoma cell lines with MEK inhibition enhances the expression of melanoma-differentiation antigens [92] and decreases the production of IL-10, IL-6, and VEGF [91].…”

Section: Mek Inhibitionmentioning

confidence: 99%

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Bedognetti

Roelands

Decock

et al. 2017

Emerging Topics in Life Sciences

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Correspondence: Davide Bedognetti (dbedognetti@sidra.org)With the advent of checkpoint inhibition, immunotherapy has revolutionized the clinical management of several cancers, but has demonstrated limited efficacy in mammary carcinoma. Transcriptomic profiling of cancer samples defined distinct immunophenotypic categories characterized by different prognostic and predictive connotations. In breast cancer, genomic alterations leading to the dysregulation of mitogen-activated protein kinase (MAPK) pathways have been linked to an immune-silent phenotype associated with poor outcome and treatment resistance. These aberrations include mutations of MAP3K1 and MAP2K4, amplification of KRAS, BRAF, and RAF1, and truncations of NF1. Anticancer therapies targeting MAPK signaling by BRAF and MEK inhibitors have demonstrated clear immunologic effects. These off-target properties could be exploited to convert the immune-silent tumor phenotype into an immune-active one. Preclinical evidence supports that MAPK-pathway inhibition can dramatically increase the efficacy of immunotherapy. In this review, we provide a detailed overview of the immunomodulatory impact of MAPK-pathway blockade through BRAF and MEK inhibitions. While BRAF inhibition might be relevant in melanoma only, MEK inhibition is potentially applicable to a wide range of tumors. Context-dependent similarities and differences of MAPK modulation will be dissected, in light of the complexity of the MAPK pathways. Therapeutic strategies combining the favorable effects of MAPK-oriented interventions on the tumor microenvironment while maintaining T-cell function will be presented. Finally, we will discuss recent studies highlighting the rationale for the implementation of MAPK-interference approaches in combination with checkpoint inhibitors and immune agonists in breast cancer.

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Section: Mek Inhibitionmentioning

confidence: 99%

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

Bedognetti

Roelands

Decock

et al. 2017

Emerging Topics in Life Sciences

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show abstract

“…It will be important to discover pharmacological modulators of HLA-I that can be used for combination therapy with TCRm Abs or other HLA-I-based immunotherapies. For example, recent reports demonstrate that inhibition of MEK can increase cell-surface HLA-I, which may enhance TCRm Ab therapy (47). Additionally, several pharmacological agents that target histone-modifying enzymes, such as methytransferase inhibitors and histone deacetylase inhibitors, can induce expression of tumor-associated antigens, including PRAME, and lead to enhanced cytolysis by effector T cells (48)(49)(50).…”

Section: Control Peptides Used Were Established Hla-a2-binding Peptidmentioning

confidence: 99%

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

Chang¹,

Dao²,

Gejman³

et al. 2017

Journal of Clinical Investigation

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“…For instance, agents such as azacytidine and epidermal growth factor receptor inhibitors promote re-expression of tumor-associated antigens in malignant cells, 7 and radiotherapy induces expression of major histocompatibility complex class I molecules, 8 which are essential to the production of tumor-specific T cells. Because of the ample evidence showing that certain anticancer therapies increase the immunogenicity of tumor cells as part of their mechanism of action, this finding may reflect a negative impact of immunosuppression on the ability of the adaptive immune system to recognize and respond to neoantigens that become manifest during tumor progression or treatment.…”

mentioning

confidence: 99%

Improving cancer‐specific outcomes in solid organ transplant recipients: Where to begin?

Koff

Waller

2019

Cancer

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In an article published in this issue of Cancer, D'Arcy et al link the incidence of cancer among recipients of solid organ transplantation (SOT) in the Scientific Registry of Transplant Recipients with data from regional and statewide cancer registries to examine cancerspecific mortality for common malignancies in SOT recipients. This analysis helps to illuminate the role of immune surveillance across a broad range of malignancies and compares the incidence of cancers due to virally mediated oncogenesis (lymphoma, squamous cell carcinoma of the aerodigestive epithelium, and hepatitis-induced liver cancer) with the incidence of other malignancies. The authors' central finding is that cancer-specific mortality is significantly increased in SOT recipients in comparison with nontransplant recipients for multiple cancers, and the increased cancer incidence is not limited to the effects of viral oncogenesis. The authors document a significant increase in common epithelial malignancies that are currently treated with immune checkpoint antibodies, including melanoma, bladder cancer, colorectal cancer, cancers of the oral cavity/pharynx, kidney cancer, and lung cancer, and this supports the hypothesis that post-SOT immunosuppression affects immune surveillance in these cancers. Provocatively, the authors also document increases in the incidence and mortality of cancers not typically responsive to immune checkpoint therapies, including breast cancer and pancreatic cancer. The findings of D'Arcy et al suggest that immune surveillance controls oncogenesis and tumor progression in a broad range of malignancies and that breast cancer and pancreatic cancer could be sensitive to drugs targeting immune surveillance pathways other than those treated with currently Food and Drug Administration-approved antibodies to CTLA4 and PD-1/PD-L1. Cancer 2019;125:838-842.

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Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells

Cited by 143 publications

References 49 publications

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

The MAPK hypothesis: immune-regulatory effects of MAPK-pathway genetic dysregulations and implications for breast cancer immunotherapy

A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens

Improving cancer‐specific outcomes in solid organ transplant recipients: Where to begin?

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