Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy

Johnson, Douglas B.; Estrada, Mónica V.; Salgado, Roberto; Sánchez, Violeta; Doxie, Deon B.; Opalenik, Susan R.; Vilgelm, Anna E.; Feld, Emily; Johnson, Adam S.; Greenplate, Allison R.; Sanders, Melinda E.; Lovly, Christine M.; Frederick, Dennie T.; Kelley, Mark C.; Richmond, Ann; Irish, Jonathan M.; Shyr, Yu; Sullivan, Ryan J.; Puzanov, Igor; Sosman, Jeffrey A.; Balko, Justin M.

doi:10.1038/ncomms10582

Cited by 446 publications

(445 citation statements)

References 48 publications

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“…21 Furthermore, melanoma-specific expression of MHC-class II genes has been shown to be associated with response to anti-PD-1 therapy. 22 MHC-class II antigen presentation is primarily involved in the activation of CD4 + T cell-based immune responses. Given the role of neoantigens in eliciting a tumor immune response, 23 and the B cell, T cell and antigen presentation functions associated with the MBL signature, it is possible that the MBL signature was detecting an MHC-class II driven immune response.…”

Section: Discussionmentioning

confidence: 99%

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

2018

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Immune checkpoint inhibitors have shown great potential in treating solid tumors, inducing durable remission and prolonged survival time in responders. Despite their promise, a large fraction of patients remains unresponsive to these treatments highlighting the need for biomarkers that can predict patient sensitivity. Pre-treatment gene expression profiles for patients receiving immune checkpoint inhibitors have recently become available, establishing a new medium by which to discover biomarkers that predict therapy response. In this study, we mined for transcriptomic correlates of response by applying immune cell-derived gene expression signatures to publicly available datasets containing matched gene expression and response efficacy information. These datasets were comprised of urothelial carcinoma patients receiving anti-PD-L1 (n = 25), melanoma patients receiving anti-PD-1 (n = 28), and melanoma patients receiving anti-CTLA-4 (n = 42). We identified one signature, derived from a subpopulation of B cells, with scores that were significantly and reproducibly elevated in patients experiencing clinical benefit following therapy targeting the PD-1/PD-L1 axis and were additionally elevated in patients responsive to anti-CTLA-4 therapy. Multivariate models revealed that this signature was associated with response independent of other response-predictive biomarkers, including tumor mutation burden. Functional annotation of the signature revealed it to be associated with features indicative of an immunologically active microenvironment, including B and T cell activation as well as antigen presentation activity. The preliminary findings presented detail a transcriptomic signature associated with response to multiple checkpoint inhibitors and suggest novel biological associations that warrant further investigation.

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Section: Discussionmentioning

confidence: 99%

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

2018

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“…Lower number of CD14+HLA-DRneg/low MDSC before treatment correlated positively with response, while an increase in MDSC during therapy was indicative of lack of response [96]. More recent evidence suggests that MHC-II expression on melanoma cells, which is easily achievable by IHC staining with commercially available antibodies for HLA-DR, is associated with therapeutic response and patient survival in melanoma [97].…”

Section: The Role Of the Microenvironment In Melanoma Heterogeneitymentioning

confidence: 99%

Contemporary and potential future molecular diagnosis of melanoma

Gandolfi¹,

Dallaglio²,

Longo

et al. 2016

Expert Review of Molecular Diagnostics

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We reviewed the most recent publications about the biology of cutaneous melanoma, to provide an overview of the most recent insights into the complexity of this tumor and their potential impact in the clinical settings. Expert commentary: Starting from the first attempts to provide a molecular classification of melanoma, it has been evident that this tumor represents a widely heterogeneous disease. This complexity and the multivariate nature of melanoma represent a major obstacle in developing the best management strategies for patients.

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“…Up-regulation of class II expression has been described for some solid tumors [42][43][44][45] and, in melanoma, is associated with increased probability of response to immune checkpoint blockade therapy. 46 Adoptive transfer of TILs enriched for CD4 + T cells specific for a mutation in erbb2-interacting protein produced striking clinical responses in a patient with metastatic cholangiocarcinoma. 47 As we learn more about class II-restricted TAAs, these too may prove to be relevant targets in hematologic malignancies.…”

Section: Antigen Targets Of T-cell Receptors For Immunotherapy Antigementioning

confidence: 99%

T-Cell Receptor–Based Immunotherapy for Hematologic Malignancies

Biernacki¹,

Brault

Bleakley³

2019

Cancer J

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Adoptive immunotherapy with engineered T cells is at the forefront of cancer treatment. T cells can be engineered to express T-cell receptors (TCRs) specific for tumor-associated antigens (TAAs) derived from intracellular or cell surface proteins. T cells engineered with TCRs (TCR-T) allow for targeting diverse types of TAAs, including proteins overexpressed in malignant cells, those with lineage-restricted expression, cancer-testis antigens, and neoantigens created from abnormal, malignancy-restricted proteins. Minor histocompatibility antigens can also serve as TAAs for TCR-T to treat relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Moreover, TCR constructs can be modified to improve safety and enhance function and persistence of TCR-T. Transgenic T-cell receptor therapies targeting 3 different TAAs are in early-phase clinical trials for treatment of hematologic malignancies. Preclinical studies of TCR-T specific for many other TAAs are underway and offer great promise as safe and effective therapies for a wide range of cancers.

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Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy

Cited by 446 publications

References 48 publications

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

Contemporary and potential future molecular diagnosis of melanoma

T-Cell Receptor–Based Immunotherapy for Hematologic Malignancies

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