Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

Gargiulo, Piera; Pepa, Chiara Della; Berardi, Simona; Califano, Daniela; Scala, Stefania; Buonaguro, Luigi; Ciliberto, Gennaro; Brauchli, Peter; Pignata, Sandro

doi:10.1016/j.ctrv.2016.06.008

Cited by 105 publications

(81 citation statements)

References 82 publications

(173 reference statements)

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“…In general, it has been recognized that these therapies are more effective against cancer types with high mutation burdens, such as melanoma (45), lung cancer (46, 47), bladder cancer, microsatellite instable (MSI) gastroesophageal cancers, and MSI- or polymerase epsilon-ultramutated endometrial (POLE) cancers (46, 49). An increased rate of mutation is more likely to alter existing antigen sequences to result in high-affinity neo-antigens that are recognized as immunogens and result in expansion of tumor-specific CD8 T cells.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with High-Affinity Epitopes Impairs Antitumor Efficacy by Increasing PD-1 Expression on CD8+ T Cells

Zahm

Colluru

McNeel

2017

Cancer Immunology Research

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Antitumor vaccines encoding self-antigens generally have low immunogenicity in clinical trials. Several approaches are aimed at improving vaccine immunogenicity, including efforts to alter encoded epitopes. Immunization with epitopes altered for increased affinity for the major histocompatibility complex (MHC) or T-cell receptor (TCR) elicits greater numbers of CD8 T cells but inferior antitumor responses. Our previous results suggested that programmed death 1 (PD-1) and its ligand (PD-L1) increased on antigen-specific CD8 T cells and tumor cells, respectively, after high-affinity vaccination. In this report, we use two murine models to investigate whether the dose, MHC affinity, or TCR affinity of an epitope affected the antitumor response via the PD-1/PD-L1 axis. T cells activated with high-affinity epitopes resulted in prolonged APC:T-cell contact time that led to elevated, persistent PD-1 expression, and expression of other checkpoint molecules, in vitro and in vivo. Immunization with high-affinity epitopes also decreased antitumor efficacy in the absence of PD-1 blockade. Thus, APC:T-cell contact time can be altered by epitope affinity and lead to therapeutically relevant changes in vaccine efficacy mediated by changes in PD-1 expression. These findings have implications for the use of agents targeting PD-1 expression or function whenever high-affinity CD8 T cells are elicited or supplied by means of vaccination or adoptive transfer.

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Section: Discussionmentioning

confidence: 99%

Vaccination with High-Affinity Epitopes Impairs Antitumor Efficacy by Increasing PD-1 Expression on CD8+ T Cells

Zahm

Colluru

McNeel

2017

Cancer Immunology Research

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“…While further studies are needed, this may indicate that immunotherapy alone, if necessary, could replace radiation and chemotherapy after surgery in these cases. We refer the reader to other, more comprehensive, reviews of this topic [91,98–100] and would like to finish by discussing additional possible therapeutic approaches suggested by mechanistic studies in model systems. In yeast, the mutator effects of both exonuclease and polymerase domain variants of Polε and Polδ are highly sensitive to even small fluctuations of dNTP levels ([73,82]; section 5).…”

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Barbari

Shcherbakova

2017

DNA Repair

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The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.

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“…Therefore, POLE ultramutated and MSI hypermutated ECs show high neoantigen load and high number of TILs, counterbalanced by PD-1 and PD-L1 overexpression. Such features could represent a strong rationale for testing immune checkpoint inhibitors in these cancer subgroups (86)(87)(88). Santin et al (89) reported a remarkable clinical response to nivolumab intwo patients with recurrent, heavily pretreated ultramutated or hypermutated endometrial cancer.…”

Section: Endometrial Cancermentioning

confidence: 99%

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

2017

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Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

Cited by 105 publications

References 82 publications

Vaccination with High-Affinity Epitopes Impairs Antitumor Efficacy by Increasing PD-1 Expression on CD8+ T Cells

Vaccination with High-Affinity Epitopes Impairs Antitumor Efficacy by Increasing PD-1 Expression on CD8+ T Cells

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

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