Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer

Sæterdal, Ingvil; Bjørheim, Jens; Lislerud, Kari; Klemp, Marianne; Bukholm, Ida K.; Olsen, Ole Christian; Nesland, Jahn M.; Eriksen, Jon Amund; Mlika, Mona; Lindblom, Annika; Gaudernack, Gustav

doi:10.1073/pnas.231326898

Cited by 241 publications

(173 citation statements)

References 22 publications

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“…MSI tumors are generally defined by their large number of somatic mutations, compared with microsatellite stable (MSS) tumors. These tumors also exhibit heavy peritumoral/intratumoral lymphocytic infiltration, most likely due to a large number of mutated antigenic epitopes at the cell surface; this observation has been previously correlated with good prognosis in early-stage disease (8).…”

Section: Introductionmentioning

confidence: 79%

Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy

Dunne

McArt

O’Reilly

et al. 2016

Cancer Immunology Research

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A recent phase II study of patients with metastatic colorectal carcinoma showed that mismatch repair gene status was predictive of clinical response to PD-1-targeting immune checkpoint blockade. Further examination revealed strong correlation between PD-L1 protein expression and microsatellite instability (MSI) in stage IV colorectal carcinoma, suggesting that the amount of PD-L1 protein expression could identify late-stage patients who might benefit from immunotherapy. To assess whether the clinical associations between PD-L1 gene expression and MSI identified in metastatic colorectal carcinoma are also present in stage II/III colorectal carcinoma, we used in silico analysis to elucidate the cell types expressing the PD-L1 gene. We found a statistically significant association of PD-L1 gene expression with MSI in early-stage colorectal carcinoma (P < 0.001) and show that, unlike in non-colorectal carcinoma tumors, PD-L1 is derived predominantly from the immune infiltrate. We demonstrate that PD-L1 gene expression has positive prognostic value in the adjuvant disease setting (PD-L1 low vs. PD-L1 high HR ¼ 9.09; CI, 2.11-39.10). PD-L1 gene expression had predictive value, as patients with high PD-L1 expression appear to be harmed by standard-of-care treatment (HR ¼ 4.95; CI, 1.10-22.35). Building on the promising results from the metastatic colorectal carcinoma PD-1-targeting trial, we provide compelling evidence that patients with PD-L1 high /MSI/ immune high stage II/III colorectal carcinoma should not receive standard chemotherapy. This conclusion supports the rationale to clinically evaluate this patient subgroup for PD-1 blockade treatment.

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Section: Introductionmentioning

confidence: 79%

Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy

Dunne

McArt

O’Reilly

et al. 2016

Cancer Immunology Research

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“…However, gastrointestinal MSI-H tumors are known to be inf lammatory neoplasms with a high content of infiltrating lymphocytes (33). This clinical fact has been related to the presence of numerous neoantigens at the tumor cell surface as a consequence of the mutator process affecting numerous target genes and leading to the synthesis of truncated proteins during tumoral progression (34). In this context, …”

Section: Discussionmentioning

confidence: 99%

The mutator pathway is a feature of immunodeficiency-related lymphomas

Duval

Raphaël

Brennetot

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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The mutator phenotype caused by defects in the mismatch repair system is observed in a subset of solid neoplasms characterized by widespread microsatellite instability-high (MSI-H). It is known to be very rare in non-Hodgkin lymphomas (NHL), whereas mutator NHL is the most frequent tumor subtype in mismatch repairdeficient mice. By screening a series of 603 human NHL with specific markers of the mutator phenotype, we found here 12 MSI-H cases (12͞603, 2%). Of interest, we demonstrated that this phenotype was specifically associated with immunodeficiency-related lymphomas (ID-RL), because it was observed in both posttransplant lymphoproliferative disorders (9͞111, 8.1%) and HIV infectionrelated lymphomas (3͞128, 2.3%) but not in a large series of NHL arising in the general population (0͞364) (P < 0.0001). The MSI pathway is known to lead to the production of hundreds of abnormal protein neoantigens that are generated in MSI-H neoplasms by frameshift mutations of a number of genes containing coding microsatellite sequences. As expected, MSI-H ID-RL were found to harbor such genetic alterations in 12 target genes with a putative role in lymphomagenesis. The observation that the MSI-H phenotype was restricted to HIV infection-related lymphomas and posttransplant lymphoproliferative disorders suggests the existence of the highly immunogenic mutator pathway as a novel oncogenic process in lymphomagenesis whose role is favored when host immunosurveillance is reduced. Because MSI-H-positive cases were found to be either Epstein-Barr virus-positive or -negative, the mutator pathway should act synergistically or not with this other oncogenic factor, playing an important role in ID-RL. microsatellite instability

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“…The abnormal peptides produced by MSI-H tumours may be presented to CD4+ T-cells by the HLA-DR molecules expressed on the cell surface. In fact, one recent study has identified a patient with an HLA-DR restricted CD4+ T-cell response against a TGFbRII frameshift peptide (Saeterdal et al, 2001). The tumour had heterogeneous HLA-DR expression with prominent CD4+ T-cell infiltration in areas positive for HLA-DR antigen, whereas relatively few cytotoxic CD8+ T-cells were present.…”

Section: Discussionmentioning

confidence: 99%

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

et al. 2002

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Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival ( P <0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability ( P <0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients. British Journal of Cancer (2002) 87 , 756–762. doi: 10.1038/sj.bjc.6600507 www.bjcancer.com © 2002 Cancer Research UK

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Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer

Cited by 241 publications

References 22 publications

Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy

Immune-Derived PD-L1 Gene Expression Defines a Subgroup of Stage II/III Colorectal Cancer Patients with Favorable Prognosis Who May Be Harmed by Adjuvant Chemotherapy

The mutator pathway is a feature of immunodeficiency-related lymphomas

Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

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