HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma

Han, Liz Y.; Fletcher, Mavis S.; Urbauer, Diana L.; Müeller, Peter R.; Landen, Charles N.; Kamat, Aparna A.; Lin, Yvonne G.; Merritt, William M.; Spannuth, Whitney A.; Deavers, Michael T.; Geest, Koen De; Gershenson, David M.; Lutgendorf, Susan K.; Ferrone, Soldano; Sood, Anil K.

doi:10.1158/1078-0432.ccr-07-4433

Cited by 135 publications

(134 citation statements)

References 32 publications

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“…[19][20][21]24 A former study has demonstrated that restoring tapasin gene expression in a mouse tumor model using viral vector transduction improved survival of model mice bearing lung carcinoma. 28 In this study, we generated human lung and colon cancer variants that express TAAs, survivin, or cep55, genetically lacking tapasin protein expression.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15][16][17][18] Notably, tapasin expression associated with intratumoral T-cell infiltration has been reported as a prognostic marker of patient survival in ovarian carcinoma, HNSCC, glioblastoma, and colorectal carcinoma. 12,13,[19][20][21] It is also reported that loss of tapasin is more frequent among the other antigen-processing machinery (APM) components, strongly suggesting its central role in escape from CTL immune surveillance to tumors. 15,22 Impaired CTL responses against tapasin-deficient cells have been well established in mouse models.…”

Section: Introductionmentioning

confidence: 99%

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Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

et al. 2017

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Cytotoxic T-lymphocytes (CTLs) lyse target cells after recognizing the complexes of peptides and MHC class I molecules (pMHC I) on cell surfaces. Tapasin is an essential component of the peptide-loading complex (PLC) and its absence influences the surface repertoire of MHC class I peptides. In the present study, we assessed tapasin expression in 85 primary tumor lesions of non-small cell lung cancer (NSCLC) patients, demonstrating that tapasin expression positively correlated with patient survival. CD8C T-cell infiltration of tumor lesions was synergistically observed with tapasin expression and correlated positively with survival. To establish a direct link between loss of tapasin and CTL recognition in human cancer models, we targeted the tapasin gene by CRISPR/Cas9 system and generated tapasin-deficient variants of human lung as well as colon cancer cells. We induced the CTLs recognizing endogenous tumor-associated antigens (TAA), survivin or cep55, and they responded to each tapasin-proficient wild type. In contrast, both CTL lines ignored the tapasin-deficient variants despite their antigen expression. Moreover, the adoptive transfer of the cep55-specific CTL line failed to prevent tumor growth in mice bearing the tapasindeficient variant. Loss of tapasin most likely limited antigen processing of TAAs and led to escape from TAA-specific CTL recognition. Tapasin expression is thus a key for CTL surveillance against human cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

et al. 2017

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“…6 Han et al immunostained components of the antigen-processing machinery (APM), including TAP1, TAP2, tapasin, HLA class I (HC-10), b2-microglobulin, CD3 C T cells, and CD8 C T cells. 7 They reported that APM component downregulation, lack of intratumoral T-cell infiltrates, and suboptimal cytoreduction were independent prognostic factors in multivariate analysis. In all previous studies, only the HLA class I heavy-chain staining using HC-10 was not an independent prognostic marker of ovarian cancer.…”

Section: Hla Class I Expression Is a Predictor Of Clinical Outcome Inmentioning

confidence: 99%

HLA class I as a predictor of clinical prognosis and CTL infiltration as a predictor of chemosensitivity in ovarian cancer

et al. 2015

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Abbreviations: CTL, cytotoxic T lymphocyte; HLA, human leukocyte antigen; MHC, major histocompatibility complex;TAA, tumor-associated antigen Cytotoxic T lymphocytes (CTLs) recognize the human leukocyte antigen (HLA) class I and antigenic peptide complex, and they play a crucial role in cancer immunity. Our recent study revealed that HLA class I downregulation is related to poorer prognosis and a low level of intratumoral CTLs is associated with platinum resistance, indicating the significance of immunological surveillance.

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“…16,17 Tumors from women with high-grade serous cancers frequently show a host immune response, and the presence of cytotoxic T lymphocytes, and T-regulatory cells is consistently associated with favorable prognosis. [18][19][20][21][22][23][24] Germline mutations in BRCA1 and BRCA2 are present in B18% of ovarian cancer patients with high-grade serous carcinoma. [25][26][27] When combined with BRCA deficiencies that result from somatic mutations or epigenetic silencing, it appears that up to half of all high-grade serous ovarian cancers (hereditary and sporadic) have BRCA dysfunction.…”

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confidence: 99%

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

et al. 2012

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We characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2 mutations (20% BRCA1 and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1 (group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P ¼ 0.0008). Among high-grade serous carcinomas, there were no differences between groups 1-3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P ¼ 0.034, 0.027). TP53 expression differed between groups (Po0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (Po0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.

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HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma

Cited by 135 publications

References 32 publications

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

Loss of tapasin in human lung and colon cancer cells and escape from tumor-associated antigen-specific CTL recognition

HLA class I as a predictor of clinical prognosis and CTL infiltration as a predictor of chemosensitivity in ovarian cancer

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

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