Association of Polymerase e–Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1

Howitt, Brooke E.; Shukla, Sachet A.; Sholl, Lynette M.; Ritterhouse, Lauren L.; Watkins, Jaclyn C; Rodig, Scott J.; Stover, Elizabeth H.; Strickland, Kyle C.; D’Andrea, Alan D.; Wu, Catherine J.; Matulonis, Ursula A.; Konstantinopoulos, Panagiotis A.

doi:10.1001/jamaoncol.2015.2151

Cited by 578 publications

(524 citation statements)

References 15 publications

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“…The results of the present study, combined with positive reports from ongoing clinical trials (4,41), suggest that inhibitors of these molecules may be considered as treatments for patients with endometrial tumors. Furthermore, the present study demonstrated that PD-L2 may be a useful target for immune suppression in a small number of patients with endometrial carcinoma, whereas both PD-L1 and B7-H4 were highly expressed in two of the analyzed tumor types, and therefore may be ideal candidate drug targets.…”

Section: B Amentioning

confidence: 53%

Expression of immune checkpoint molecules in endometrial carcinoma

Liu

Wang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The main obstacle in the development of an effective tumor vaccine is the inherent ability of tumors to evade immune responses. Tumors often use common immune mechanisms and regulators to evade the immune system. The present study aimed to analyze the expression levels of indoleamine 2,3-dioxygenase (IDO), programmed death-ligand (PD-L) 1, PD-L2, B7-H4, galectin-1 and galectin-3 in tissue samples from patients with endometrial carcinoma, in order to detect the immunosuppressive environment of endometrial carcinomas. The levels of IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemical methods, and the levels of galectin-1 and galectin-3 in tumor lysates were determined using ELISA. PD-L2 was expressed at low levels in the majority of tumor samples. IDO expression was detected in 38, 63 and 43% of primary endometrial carcinoma, recurrent endometrial carcinoma, and metastatic endometrial carcinoma specimens, respectively. Positive expression rates for PD-L1 were 83% in primary endometrial carcinoma, 68% in recurrent endometrial carcinoma, and 100% in metastatic endometrial carcinoma, whereas B7-H4 expression was detected in 100% of both primary endometrial carcinoma and recurrent endometrial carcinoma samples, and in 96% of metastatic endometrial carcinoma specimens. The expression levels of galectin-1 and galectin-3 were not significantly different between the normal and tumor specimens. The results of the present study suggest that the interaction between PD-1/PD-L1 and B7-H4 may be a potential target for immune intervention in the treatment of endometrial carcinoma. Furthermore, the results may provide the basis for immunosuppressant therapy in the treatment of patients with uterine cancer.

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Section: B Amentioning

confidence: 53%

Expression of immune checkpoint molecules in endometrial carcinoma

Liu

Wang

et al. 2015

Experimental and Therapeutic Medicine

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“…The increased tumor‐infiltrating lymphocytes observed in MSI‐high CRC are themselves a sign of immune activation, and it has been hypothesized that the increased mutational burden seen in these tumors could predict immunogenicity and response to immune checkpoint blockade. It is estimated that POLE mutated tumors on average have 15‐fold more neoantigens than MSI tumors and 100‐fold more than typical MSS tumors [17], [18]. …”

Section: Molecular Tumor Boardmentioning

confidence: 99%

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Castellucci

Goldstein

et al. 2017

The Oncologist

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Two cases of metastatic colorectal cancer with a POLE mutation, both of which were ultramutated and microsatellite stable, are presented and discussed from the standpoint of the basic biochemical mechanisms leading to a unique phenotype in POLE deficiency, the challenges faced with interpreting the genomic profiling of tumors in this important subset of patients, and the potential clinical implications.

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“…Somatic POLE exonuclease domain mutations (hereafter simply referred to as POLE mutations) occur in sporadic tumours of the endometrium (7–15% cases) 8, 9, colorectum (1–2%) 10, 11, and, less commonly, in other cancers (although, for reasons that are unclear, somatic POLD1 exonuclease domain mutations are very uncommon). POLE ‐mutant colorectal and endometrial cancers have an excellent prognosis 8, 11, 12, 13, probably owing to a robust antitumour immune response against the multitude of immunogenic neoantigens that they are predicted to harbour 11, 14, 15. Very recent reports have also suggested that these tumours may be highly responsive to immune checkpoint inhibition 16.…”

Section: Introductionmentioning

confidence: 99%

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Temko

Gool

Rayner

et al. 2018

The Journal of Pathology

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Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non‐malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE‐mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE‐mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T‐cell infiltrate present in POLE‐mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Association of Polymerase e–Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1

Cited by 578 publications

References 15 publications

Expression of immune checkpoint molecules in endometrial carcinoma

Expression of immune checkpoint molecules in endometrial carcinoma

DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

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