Potential MMP2-mediated availability of HLA binding, mutant ECM peptides reflects better melanoma survival rates and greater T-cell infiltrates

Zaman, Saif; Chobrutskiy, Boris I.; Patel, Jay S.; Callahan, Blake M.; Mihyu, Moody M.; Diviney, Andrea; Blanck, George

doi:10.1038/s41374-019-0248-3

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…Increased expression of COL1A2, MMP2, PCOLCE, DCN, FBLN5, SIGLEC1, and HPSE was associated with longer OS (Fig 3B), and MMP2, COL1A2, PCOLCE, and DCN with longer RFS (S3A Fig) . The extracellular matrix, including collagen, fibronectin, decorin, and related regulatory enzymes (e.g. MMPs), is the most abundant component in tumor microenvironment that can regulate tumor cell progression [72][73][74]. While higher MMP2 expression was associated with prolonged OS and RFS, post-treatment expression of another metalloproteinase ADAM15 was significantly low in both pathologic and radiologic non-responders (Figs 5C and S4B), implying a beneficial role of these metalloproteinases in response to ipilimumab and HDI therapy.…”

Section: Discussionmentioning

confidence: 99%

CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma

et al. 2021

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Patients with locally/regionally advanced melanoma were treated with neoadjuvant combination immunotherapy with high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens were obtained prior to the initiation of neoadjuvant therapy, at the time of surgery and progression if available. In this study, gene expression profiles of tumor specimens (N = 27) were investigated using the NanoString nCounter® platform to evaluate associations with clinical outcomes (pathologic response, radiologic response, relapse-free survival (RFS), and overall survival (OS)) and define biomarkers associated with tumor response. The Tumor Inflammation Signature (TIS), an 18-gene signature that enriches for response to Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated for association with clinical response and survival. It was observed that neoadjuvant ipilimumab-HDI therapy demonstrated an upregulation of immune-related genes, chemokines, and transcription regulator genes involved in immune cell activation, function, or cell proliferation. Importantly, increased expression of baseline pro-inflammatory genes CCL19, CD3D, CD8A, CD22, LY9, IL12RB1, C1S, C7, AMICA1, TIAM1, TIGIT, THY1 was associated with longer OS (p < 0.05). In addition, multiple genes that encode a component or a regulator of the extracellular matrix such as MMP2 and COL1A2 were identified post-treatment as being associated with longer RFS and OS. In all baseline tissues, high TIS scores were associated with longer OS (p = 0.0166). Also, downregulated expression of cell proliferation-related genes such as CUL1, CCND1 and AAMP at baseline was associated with pathological and radiological response (unadjusted p < 0.01). In conclusion, we identified numerous genes that play roles in multiple biological pathways involved in immune activation, immune suppression and cell proliferation correlating with pathological/radiological responses following neoadjuvant immunotherapy highlighting the complexity of immune responses modulated by immunotherapy. Our observations suggest that TIS may be a useful biomarker for predicting survival outcomes with combination immunotherapy.

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Section: Discussionmentioning

confidence: 99%

CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma

et al. 2021

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“…The high-affinity interaction with Human leukocyte antigens (HLA) class I molecules would promote antitumor T cell immune response. 52…”

Section: Mmp-2mentioning

confidence: 99%

“…Arrest of oncogenic cellular events and induction of autophagy in BRAF-and NRAS-mutated melanoma cells 34 Blockade of oncogenic PI3K/AKT/mTOR pathway via BAG3 interaction 35 Peng et al 42 Muniz-Bongers et al 43 Zaman et al 52…”

Section: Anti-tumoralmentioning

confidence: 99%

“…Antitumor immunity suppression via CAFs and via deleterious TLR2-and TLR4-signaling 42,43 Anti-tumoral Promotion of anti-tumor T cell immunity by release of ECM structural protein mutants 52 Tomonobu et al 58 Chen et al 60…”

Section: Pro-tumoralmentioning

confidence: 99%

“…On the other hand, the controversial and dual role of MMP2 emerges from its association with improved overall survival rates in melanoma patients with a higher mutation burden due to its activity of freeing extracellular matrix (ECM) structural protein mutants adjacent to MMP2‐sensitive sites. The high‐affinity interaction with Human leukocyte antigens (HLA) class I molecules would promote anti‐tumor T cell immune response 52 …”

Section: Introductionmentioning

confidence: 99%

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Alarmins in cutaneous malignant melanoma: An updated overview of emerging evidence on their pathogenetic, diagnostic, prognostic, and therapeutic role

Papa,

Li Pomi,

Borgia

et al. 2024

The Journal of Dermatology

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Malignant cutaneous melanoma is the leading cause of death for skin cancer to date, with globally increasing incidence rates. In this epidemiological scenario, international scientific research is exerting efforts to identify new clinical strategies aimed at the prognostic amelioration of the disease. Very promising and groundbreaking in this context is the scientific interest related to alarmins and their pioneering utility in the setting of the pathogenetic understanding, diagnosis, prognosis, and therapy for malignant cutaneous melanoma. However, the scientific investigations on this matter should not overlook their still well‐presented dual and contradictory role. The aim of our critical analysis is to provide an up‐to‐date overview of the emerging evidence concerning the dichotomous role of alarmins in the aforementioned clinical settings. Our literature revision was based on the extensive body of both preclinical and clinical findings published on the PubMed database over the past 5 years. In addition to this, we offer a special focus on potentially revolutionary new therapeutic frontiers, which, on the strength of their earliest successes in other clinical areas, could inaugurate a new era of personalized and precision medicine in the field of dermato‐oncology.

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TRBV and TRBJ usage, when paired with specific HLA alleles, associates with distinct head and neck cancer survival rates

et al. 2020

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Potential MMP2-mediated availability of HLA binding, mutant ECM peptides reflects better melanoma survival rates and greater T-cell infiltrates

Cited by 6 publications

References 20 publications

CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma

CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma

Alarmins in cutaneous malignant melanoma: An updated overview of emerging evidence on their pathogenetic, diagnostic, prognostic, and therapeutic role

TRBV and TRBJ usage, when paired with specific HLA alleles, associates with distinct head and neck cancer survival rates

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