The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investig...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2017-08-01
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| Series: | OncoImmunology |
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| Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1338996 |
| _version_ | 1818026658345517056 |
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| author | Hirokazu Matsushita Kosei Hasegawa Katsutoshi Oda Shogo Yamamoto Akira Nishijima Yuichi Imai Kayo Asada Yuji Ikeda Takahiro Karasaki Keiichi Fujiwara Hiroyuki Aburatani Kazuhiro Kakimi |
| author_facet | Hirokazu Matsushita Kosei Hasegawa Katsutoshi Oda Shogo Yamamoto Akira Nishijima Yuichi Imai Kayo Asada Yuji Ikeda Takahiro Karasaki Keiichi Fujiwara Hiroyuki Aburatani Kazuhiro Kakimi |
| author_sort | Hirokazu Matsushita |
| collection | DOAJ |
| description | Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation (“neoAg frequency”) did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC (p = 0.032), especially at stage I-II (p = 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and -C expression (p = 0.036, p = 0.026, and p = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression (p = 0.0064, p = 0.017, p = 0.033 and p = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agent-based treatments. |
| first_indexed | 2024-12-10T04:35:30Z |
| format | Article |
| id | doaj.art-904bf863f2eb4b7bbd41ffa40ff2d623 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-10T04:35:30Z |
| publishDate | 2017-08-01 |
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| series | OncoImmunology |
| spelling | doaj.art-904bf863f2eb4b7bbd41ffa40ff2d6232022-12-22T02:02:02ZengTaylor & Francis GroupOncoImmunology2162-402X2017-08-016810.1080/2162402X.2017.13389961338996The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinomaHirokazu Matsushita0Kosei Hasegawa1Katsutoshi Oda2Shogo Yamamoto3Akira Nishijima4Yuichi Imai5Kayo Asada6Yuji Ikeda7Takahiro Karasaki8Keiichi Fujiwara9Hiroyuki Aburatani10Kazuhiro Kakimi11The University of Tokyo HospitalSaitama Medical University International Medical CenterThe University of Tokyo HospitalThe University of TokyoThe University of Tokyo HospitalSaitama Medical University International Medical CenterThe University of Tokyo HospitalSaitama Medical University International Medical CenterThe University of Tokyo HospitalSaitama Medical University International Medical CenterThe University of TokyoThe University of Tokyo HospitalNeoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation (“neoAg frequency”) did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC (p = 0.032), especially at stage I-II (p = 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and -C expression (p = 0.036, p = 0.026, and p = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression (p = 0.0064, p = 0.017, p = 0.033 and p = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agent-based treatments.http://dx.doi.org/10.1080/2162402X.2017.1338996immune signaturemissense mutationneoantigenneoantigen frequencyovarian clear cell carcinomaprognostic factor |
| spellingShingle | Hirokazu Matsushita Kosei Hasegawa Katsutoshi Oda Shogo Yamamoto Akira Nishijima Yuichi Imai Kayo Asada Yuji Ikeda Takahiro Karasaki Keiichi Fujiwara Hiroyuki Aburatani Kazuhiro Kakimi The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma OncoImmunology immune signature missense mutation neoantigen neoantigen frequency ovarian clear cell carcinoma prognostic factor |
| title | The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma |
| title_full | The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma |
| title_fullStr | The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma |
| title_full_unstemmed | The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma |
| title_short | The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma |
| title_sort | frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma |
| topic | immune signature missense mutation neoantigen neoantigen frequency ovarian clear cell carcinoma prognostic factor |
| url | http://dx.doi.org/10.1080/2162402X.2017.1338996 |
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