Can Immune Suppression and Epigenome Regulation in Placenta Offer Novel Insights into Cancer Immune Evasion and Immunotherapy Resistance?

Hossain, Sultana Mehbuba; Lynch-Sutherland, Chiemi F.; Chatterjee, Aniruddha; Macaulay, Erin C.; Eccles, Michael R.

doi:10.3390/epigenomes5030016

Cited by 6 publications

(4 citation statements)

References 218 publications

(277 reference statements)

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“…Supporting this, responder melanomas were highly enriched with a combination of CD8+ T cells, T helper cells (Th1 and Th2), dendritic cells (DCs) and an M1 subtype of macrophages, whereas non-responding tumours contained abundant M2 macrophages and B cells. Th1 cells, IFN-γ, and TNFα regulate M1 macrophages to enhance antigen presentation on the major histocompatibility complex (MHC) ( 70 , 71 ) to exert anti-tumour immune response. In contrast, activated M2 macrophage subtypes possess pro-tumorigenic properties ( 72 , 73 ).…”

Section: Discussionmentioning

confidence: 99%

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

et al. 2022

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Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body’s immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures. We performed multi-omics investigations on melanoma tumour tissues, which were collected from patients before starting treatment with anti-PD1 immune checkpoint inhibitors. Patients were subsequently categorized into responders and non-responders to anti-PD1 therapy based on RECIST criteria. Multi-omics analyses included RNA-Seq and NanoString analysis. From RNA-Seq data we carried out HLA phenotyping as well as gene enrichment analysis, pathway enrichment analysis and immune cell deconvolution studies. Consistent with previous studies, our data showed that responders to anti-PD1 therapy had higher immune scores (median immune score for responders = 0.1335, median immune score for non-responders = 0.05426, p-value = 0.01, Mann-Whitney U two-tailed exact test) compared to the non-responders. Responder melanomas were more highly enriched with a combination of CD8+ T cells, dendritic cells (p-value = 0.03) and an M1 subtype of macrophages (p-value = 0.001). In addition, melanomas from responder patients exhibited a more differentiated gene expression pattern, with high proliferative- and low invasive-associated gene expression signatures, whereas tumours from non-responders exhibited high invasive- and frequently neural crest-like cell type gene expression signatures. Our findings suggest that non-responder melanomas to anti-PD1 therapy exhibit a de-differentiated gene expression signature, associated with poorer immune cell infiltration, which establishes a gene expression pattern characteristic of innate resistance to anti-PD1 therapy. Improved understanding of tumour-intrinsic gene expression patterns associated with response to anti-PD1 therapy will help to identify predictive biomarkers of ICI response and may help to identify new targets for anticancer treatment, especially with a capacity to function as adjuvants to improve ICI outcomes.

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Section: Discussionmentioning

confidence: 99%

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

et al. 2022

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“…Future clinical trials could include a series of CEST peptides, each producing novel antigens, to limit the immune response of chronic MRI patients. In addition, investigating and elucidating the limited immune response to human placental cells 47 could provide unique insights into future diagnostic applications of these CEST reporters. It is also possible that immune response may not be a limitation for some preclinical studies—for example, in cases where immune responses might be beneficial, such as oncolytic virotherapy.…”

Section: Resultsmentioning

confidence: 99%

Development of a synthetic biosensor for chemical exchange MRI utilizing in silico optimized peptides

et al. 2023

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Chemical exchange saturation transfer (CEST) MRI has been identified as a novel alternative to classical diagnostic imaging. Over the last several decades, many studies have been conducted to determine possible CEST agents, such as endogenously expressed compounds or proteins, that can be utilized to produce contrast with minimally invasive procedures and reduced or non‐existent levels of toxicity. In recent years there has been an increased interest in the generation of genetically engineered CEST contrast agents, typically based on existing proteins with CEST contrast or modified to produce CEST contrast. We have developed an in silico method for the evolution of peptide sequences to optimize CEST contrast and showed that these peptides could be combined to create de novo biosensors for CEST MRI. A single protein, superCESTide, was designed to be 198 amino acids. SuperCESTide was expressed in E. coli and purified with size exclusion chromatography. The magnetic transfer ratio asymmetry generated by superCESTide was comparable to levels seen in previous CEST reporters, such as protamine sulfate (salmon protamine) and human protamine. These data show that novel peptides with sequences optimized in silico for CEST contrast that utilize a more comprehensive range of amino acids can still produce contrast when assembled into protein units expressed in complex living environments.

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“…Future clinical trials could include a series of CEST peptides, each producing novel antigens, to limit the immune response of chronic MRI patients. In addition, investigating and elucidating the limited immune response to human placental cells 46 could provide unique insights into future diagnostic applications of these CEST reporters. It is also possible that immune response may not be a limitation for some pre-clinical studies, such as in cases where immune responses might be beneficial, like oncolytic virotherapy.…”

Section: -Size Exclusion Chromatography For Purificationmentioning

confidence: 99%

Development of a Synthetic Biosensor for Chemical Exchange MRI UtilizingIn SilicoOptimized Peptides

Fillion

Bricco

Lee

et al. 2023

Preprint

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Chemical Exchange Saturation Transfer (CEST) magnetic resonance imaging (MRI) has been identified as a novel alternative to classical diagnostic imaging. Over the last several decades, many studies have been conducted to determine possible CEST agents, such as endogenously expressed compounds or proteins, that can be utilized to produce contrast with minimally invasive procedures and reduced or non-existent levels of toxicity. In recent years there has been an increased interest in the generation of genetically engineered CEST contrast agents, typically based on existing proteins with CEST contrast or modified to produce CEST contrast. We have developed an in-silico method for the evolution of peptide sequences to optimize CEST contrast and showed that these peptides could be combined to create de novo biosensors for CEST MRI. A single protein, superCESTide 2.0, was designed to be 198 amino acids. SuperCESTide 2.0 was expressed in E. coli and purified with size-exclusion chromatography. The magnetic transfer ratio asymmetry (MTRasym) generated by superCESTide 2.0 was comparable to levels seen in previous CEST reporters, such as protamine sulfate (salmon protamine, SP), Poly-L-Lysine (PLL), and human protamine (hPRM1). This data shows that novel peptides with sequences optimized in silico for CEST contrast that utilizes a more comprehensive range of amino acids can still produce contrast when assembled into protein units expressed in complex living environments.

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Can Immune Suppression and Epigenome Regulation in Placenta Offer Novel Insights into Cancer Immune Evasion and Immunotherapy Resistance?

Cited by 6 publications

References 218 publications

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Development of a synthetic biosensor for chemical exchange MRI utilizing in silico optimized peptides

Development of a Synthetic Biosensor for Chemical Exchange MRI UtilizingIn SilicoOptimized Peptides

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