Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study)
Background Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid c...
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| Language: | English |
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BMJ Publishing Group
2024-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/11/e010174.full |
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| author | Naoki Takahashi Hirokazu Shoji Kengo Nagashima Hiroshi Imazeki Narikazu Boku Takeshi Kawakami Kei Muro Takeru Wakatsuki Chie Kudo-Saito Yukiya Narita Kai Tsugaru Yusuke Amanuma Naohiro Okano Yoshiyuki Yamamoto Rika Kizawa Kazunori Aoki |
| author_facet | Naoki Takahashi Hirokazu Shoji Kengo Nagashima Hiroshi Imazeki Narikazu Boku Takeshi Kawakami Kei Muro Takeru Wakatsuki Chie Kudo-Saito Yukiya Narita Kai Tsugaru Yusuke Amanuma Naohiro Okano Yoshiyuki Yamamoto Rika Kizawa Kazunori Aoki |
| author_sort | Naoki Takahashi |
| collection | DOAJ |
| description | Background Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient’s immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.Methods We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.Results We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1+ and CTLA4+ myeloid subsets within tumors at baseline, PDL1+, B7H3+ and CD115+ myeloid subsets in peripheral blood at baseline, and LAG3+, CD155+ and CD115+ myeloid subsets in peripheral blood at post-treatment.Conclusions This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC. |
| format | Article |
| id | doaj-art-d0862983d935473cb6e85adbf0ac9cc5 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d0862983d935473cb6e85adbf0ac9cc52024-11-11T03:40:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-11-01121110.1136/jitc-2024-010174Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study)Naoki Takahashi0Hirokazu Shoji1Kengo Nagashima2Hiroshi Imazeki3Narikazu Boku4Takeshi Kawakami5Kei Muro6Takeru Wakatsuki7Chie Kudo-Saito8Yukiya Narita9Kai Tsugaru10Yusuke Amanuma11Naohiro Okano12Yoshiyuki Yamamoto13Rika Kizawa14Kazunori Aoki153Saitama Cancer Center, Saitama, JapanGastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, JapanResearch Center for Medical and Health Data Science, The Institute of Statistical Mathematics, Tachikawa, Tokyo, JapanDepartment of Immune Medicine, National Cancer Center Research Institute, Tokyo, JapanDepartment of Oncology and General Medicine, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, JapanDivision of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-gun, Shizuoka, Japan9 Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, JapanDepartment of Gastroenterology, Cancer Institute Hospital Gastroenterology Center, Koto-ku, Tokyo, JapanDepartment of Immune Medicine, National Cancer Center Research Institute, Tokyo, JapanDepartment of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan2Keio University Hospital, Tokyo, Japan5Chiba Cancer Center, Chiba, Japan7Kyorin University Faculty of Medicine, Tokyo, Japan9University of Tsukuba Hospital, Ibaraki, Japan10Toranomon Hospital, Tokyo, Japan1National Cancer Center, Tokyo, JapanBackground Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient’s immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.Methods We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.Results We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1+ and CTLA4+ myeloid subsets within tumors at baseline, PDL1+, B7H3+ and CD115+ myeloid subsets in peripheral blood at baseline, and LAG3+, CD155+ and CD115+ myeloid subsets in peripheral blood at post-treatment.Conclusions This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC.https://jitc.bmj.com/content/12/11/e010174.full |
| spellingShingle | Naoki Takahashi Hirokazu Shoji Kengo Nagashima Hiroshi Imazeki Narikazu Boku Takeshi Kawakami Kei Muro Takeru Wakatsuki Chie Kudo-Saito Yukiya Narita Kai Tsugaru Yusuke Amanuma Naohiro Okano Yoshiyuki Yamamoto Rika Kizawa Kazunori Aoki Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study) Journal for ImmunoTherapy of Cancer |
| title | Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study) |
| title_full | Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study) |
| title_fullStr | Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study) |
| title_full_unstemmed | Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study) |
| title_short | Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study) |
| title_sort | myeloid subsets impede the efficacy of anti pd1 therapy in patients with advanced gastric cancer wjog10417gtr study |
| url | https://jitc.bmj.com/content/12/11/e010174.full |
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