MHC-I genotype drives early immune selection of oncogenic mutations

Marty, Rachel; Prisco, Nicola de; Carter, Hannah; Font-Burgada, Joan

doi:10.1080/23723556.2017.1409863

Cited by 3 publications

(8 citation statements)

References 10 publications

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“… 8 T-cells against driver mutations have been limited in some settings, presumably due to selection based on HLA genotype. 21 In order to test whether the BRAF V600E mutation could be immunogenic in pediatric tumors, we synthesized peptides encompassing this mutation and used these to detect and expand BRAF V600E -specific T-cells in culture. In a patient with BRAF V600E -mutant LGG and available fresh T-cells, we could demonstrate the presence of V600E-specific T-cell immunity ( online supplementary figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

Robinson

Vasquez

Kaushal

et al. 2020

J Immunother Cancer

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Brain tumors are the leading cause of cancer-related mortality in children and have distinct genomic and molecular features compared with adult glioma. However, the properties of immune cells in these tumors has been vastly understudied compared with their adult counterparts. We combined multiplex immunofluorescence immunohistochemistry coupled with machine learning and single-cell mass cytometry to evaluate T-cells infiltrating pediatric glial tumors. We show that low-grade tumors are characterized by greater T-cell density compared with high-grade glioma (HGG). However, even among low-grade tumors, T-cell infiltration can be highly variable and subtype-dependent, with greater T-cell density in pleomorphic xanthoastrocytoma and ganglioglioma. CD3+ T-cell infiltration correlates inversely with the expression of SOX2, an embryonal stem cell marker commonly expressed by glial tumors. T-cells within both HGG and low-grade glioma (LGG) exhibit phenotypic heterogeneity and tissue-resident memory T-cells consist of distinct subsets of CD103+ and TCF1+ cells that exhibit distinct spatial localization patterns. TCF1+ T-cells are located closer to the vessels while CD103+ resident T-cells reside within the tumor further away from the vasculature. Recurrent tumors are characterized by a decline in CD103+ tumor-infiltrating T-cells. BRAFV600E mutation is immunogenic in children with LGG and may serve as a target for immune therapy. These data provide several novel insights into the subtype-dependent and grade-dependent changes in immune architecture in pediatric gliomas and suggest that harnessing tumor-resident T-cells may be essential to improve immune control in glioma.

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Section: Resultsmentioning

confidence: 99%

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

Robinson

Vasquez

Kaushal

et al. 2020

J Immunother Cancer

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“…After validating the accuracy of the developed classification approach, we aimed to demonstrate its applicability in current molecular biology research. A central controversy in the context of tumor immunology is whether the individual's HLA type influences the mutational landscape of cancers 12–14,37 . With the developed approach, we determined the HLA‐A *02 status of an independent cohort of 73 MSI CRC samples.…”

Section: Resultsmentioning

confidence: 99%

“…However, by determining the repertoire of tumor antigens presented on the cell surface, HLA genotype might also influence the course of cancer progression and the mutational spectrum of arising tumor cell clones during carcinogenetic evolution. Recent studies reported an HLA type‐dependent negative selection of oncogenic mutations, predominantly examining missense mutations 12–14 . In clinical cancer research, investigating HLA type as a predictive marker for the response to immune checkpoint inhibitors has recently gained attention 15 .…”

Section: Introductionmentioning

confidence: 99%

A simple approach for detecting *HLA‐A**02 alleles in archival formalin‐fixed paraffin‐embedded tissue samples and an application example for studying cancer immunoediting

Witt

Haupt

Ahadova

et al. 2022

HLA

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33867cancer. In archival formalin-fixed paraffin-embedded (FFPE) tissue, the HLA type is difficult to analyze because of fragmentation of DNA, hindering the application of commonly used assays that rely on long DNA stretches. Addressing these difficulties, we present a refined approach for characterizing presence or absence of HLA-A*02, the most common HLA-A allele in the Caucasian population, in archival samples. We validated our genotyping strategy in a cohort of 90 samples with HLA status obtained by an NGS-based method. 90% (n = 81) of the samples could be analyzed with the approach. For all of them, the presence or absence of HLA-A*02 alleles was correctly determined with the method, demonstrating 100% sensitivity and specificity (95% CI: 91.40%-100% and 91.19%-100%). Furthermore, we provide an example of application in an independent cohort of 73 FFPE microsatellite-unstable (MSI) colorectal cancer samples. As MSI cancer cells encompass a high number of mutations in coding microsatellites, leading to the generation of highly immunogenic frameshift peptide antigens, they are ideally suited for studying relations between the mutational landscape of tumor cells and interindividual differences in the immune system, including the HLA genotype. Overall, our method can help to promote studying HLA type-dependency during the pathogenesis of a wide range of diseases, making archival and historic tissue samples accessible for identifying HLA-A*02 alleles.

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“…231 In tumor cells, autophagy leads to immunogenic cell death by surface exposure of calreticulin (ecto-CRT), secretion of ATP, and release of apoptotic proteins such as HMGB1. 232,233 On the other hand, autophagy can also suppress immune responses. 34 Lysosomal acidification in distinct phases of the pathways that lead to antigen presentation is needed and this need depends heavily on the nature of the antigen.…”

Section: Impact Of Cq On Antitumor Immune Responsesmentioning

confidence: 99%

“…64 MHC-I-driven presentation, which tends to be promoted by CQ, exposes cancer-derived neoantigens to the immune system. 232,233 On the other hand, autophagy can also suppress immune responses. Autophagy, especially under hypoxia, permits activation of transcription factor STAT3, leading to the expression and secretion of cytokines such as IL-10, and a number of other factors with immunosuppressive effects that help cancer cells escape multiple components of the immune system.…”

Section: Impact Of Cq On Antitumor Immune Responsesmentioning

confidence: 99%

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

2019

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Chloroquines are 4-aminoquinoline-based drugs mainly used to treat malaria. At pharmacological concentrations, they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article, we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.

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MHC-I genotype drives early immune selection of oncogenic mutations

Cited by 3 publications

References 10 publications

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

A simple approach for detecting *HLA‐A**02 alleles in archival formalin‐fixed paraffin‐embedded tissue samples and an application example for studying cancer immunoediting

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

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MHC-I genotype drives early immune selection of oncogenic mutations

Cited by 3 publications

References 10 publications

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

A simple approach for detecting HLA‐A*02 alleles in archival formalin‐fixed paraffin‐embedded tissue samples and an application example for studying cancer immunoediting

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

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A simple approach for detecting *HLA‐A**02 alleles in archival formalin‐fixed paraffin‐embedded tissue samples and an application example for studying cancer immunoediting