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J. Immunother. Cancer, 26 February 2025 | https://doi.org/10.1136/jitc-2024-010193
Enhanced thrombopoiesis supplies PD-L1 to circulating immune cells via the generation of PD-L1-expressing platelets in patients with lung cancer
Sung-Woo Lee,1,2,3 Saei Jeong,1,2,3,4 Young Ju Kim,1,2,3,4 Jeong Eun Noh,1,2,3,4 Kyung Na Rho,1,2,3,4 Hee-Ok Kim,5 Hyun-Ju Cho,6,7 Deok Hwan Yang,6,7 Eu Chang Hwang,7,8 Woo Kyun Bae,6,7 Sook Jung Yun,7,9 Ju Sik Yun,7,10 Cheol-Kyu Park,6,7 In-Jae Oh,6,7 Jae-Ho Cho1,2,3,4
1Department of Microbiology and Immunology, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
2Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
3National Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
4BioMedical Sciences Graduate Program, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
5Selecxine Inc, Seoul, Korea (the Republic of)
6Department of Internal Medicine, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
7Chonnam National University Hwasun Hospital, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
8Department of Urology, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
9Department of Dermatology, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
10Thoracic and Cardiovascular Surgery, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
S-WL and SJ are joint first authors.
Correspondence to Dr Sung-Woo Lee; Professor In-Jae Oh; Professor Jae-Ho Cho
1Department of Microbiology and Immunology, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
2Medical Research Center for Combinatorial Tumor Immunotherapy, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
3National Immunotherapy Innovation Center, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
4BioMedical Sciences Graduate Program, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
5Selecxine Inc, Seoul, Korea (the Republic of)
6Department of Internal Medicine, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
7Chonnam National University Hwasun Hospital, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
8Department of Urology, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
9Department of Dermatology, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
10Thoracic and Cardiovascular Surgery, Chonnam National University Medical School, Hwasun-eup, Hwasun-gun, Jeollanam-do, Korea (the Republic of)
S-WL and SJ are joint first authors.
Correspondence to Dr Sung-Woo Lee; Professor In-Jae Oh; Professor Jae-Ho Cho
Abstract
Background The increased expression of programmed cell death ligand 1 (PD-L1) on a subset of immune cells in the peripheral blood has been frequently observed in patients with cancer, suggesting a relationship with PD-L1 expression in tumor tissues. In this study, we investigated the mechanisms underlying PD-L1 expression on various types of immune cells in the peripheral blood of patients with cancer.
Methods PD-L1 expression on various immune cell populations was analyzed in peripheral blood mononuclear cells of 112 patients with non-small cell lung cancer (NSCLC) using flow cytometry. A mouse model of X-ray-induced acute thrombocytopenia was used to investigate the relationship between thrombopoiesis and PD-L1-expressing platelet generation. The clinical significance of PD-L1-expressing platelets was analyzed in a cohort of patients with stage IV NSCLC who received a combination of anti-programmed cell death 1 (PD-1) therapy and chemotherapy.
Results All immune cell populations, including monocytes, T cells, B cells, and NK cells, showed higher PD-L1 expression in patients with cancer than in healthy controls. However, this increased frequency of PD-L1-expressing cells was not attributed to the expression of the cells themselves. Instead, it was entirely dependent on the direct interaction of the cells with PD-L1-expressing platelets. Notably, the platelet-dependent acquisition of PD-L1 on circulating immune cells of patients with lung cancer was observed in various other cancer types and was mechanistically associated with a surge in thrombopoiesis, resulting in the increased production of PD-L1-expressing reticulated platelets. Clinically, patients with enhanced thrombopoiesis and concurrently high PD-L1-expressing platelets exhibited a better response to anti-PD-1 therapy.
Conclusions These findings highlight the role of tumor-associated thrombopoiesis in generating PD-L1-expressing platelets that may serve as a resource for PD-L1-positive cells in the circulation and act as a predictive biomarker for anti-PD-1/PD-L1 therapy.
Methods PD-L1 expression on various immune cell populations was analyzed in peripheral blood mononuclear cells of 112 patients with non-small cell lung cancer (NSCLC) using flow cytometry. A mouse model of X-ray-induced acute thrombocytopenia was used to investigate the relationship between thrombopoiesis and PD-L1-expressing platelet generation. The clinical significance of PD-L1-expressing platelets was analyzed in a cohort of patients with stage IV NSCLC who received a combination of anti-programmed cell death 1 (PD-1) therapy and chemotherapy.
Results All immune cell populations, including monocytes, T cells, B cells, and NK cells, showed higher PD-L1 expression in patients with cancer than in healthy controls. However, this increased frequency of PD-L1-expressing cells was not attributed to the expression of the cells themselves. Instead, it was entirely dependent on the direct interaction of the cells with PD-L1-expressing platelets. Notably, the platelet-dependent acquisition of PD-L1 on circulating immune cells of patients with lung cancer was observed in various other cancer types and was mechanistically associated with a surge in thrombopoiesis, resulting in the increased production of PD-L1-expressing reticulated platelets. Clinically, patients with enhanced thrombopoiesis and concurrently high PD-L1-expressing platelets exhibited a better response to anti-PD-1 therapy.
Conclusions These findings highlight the role of tumor-associated thrombopoiesis in generating PD-L1-expressing platelets that may serve as a resource for PD-L1-positive cells in the circulation and act as a predictive biomarker for anti-PD-1/PD-L1 therapy.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-27)
- 국내 연구진
- 생명과학 > 면역학
관련 웨비나
![폐암 환자에서 혈소판의 새로운 역할: 전신 면역 억제를 유도하는 혈중 PD-L1의 주요 공급원 [J. Immunother. Cancer]](/upload/board/files/onseminar/thumb/thumb_0000925.png)
학술웨비나
폐암 환자에서 혈소판의 새로운 역할: 전신 면역 억제를 유도하는 혈중 PD-L1의 주요 공급원 [J. Immunother. Cancer] 면역체계는 면역세포가 공격 대상 이외에 자기 자신을 공격하지 못하도록 하는 자기 방어 기전을 갖추고 있습니다. 특히 PD-L1은 대표적인 자기 방어 수단으로, 우리 몸의 다양한 세포에서 발현되어 중요한 역할을 수행합니다. 그러나 우리 몸에서 유래된 암세포 또한 PD-L1을 발현하여 면역세포로부터 회피하는 데 이용되며, 면역세포 자체에서도 PD-L1 발현이 관찰되어 면역 공격을 억제함으로써 암의 성장을 촉진하는 것으로 알려져 있습니다. 저희는 비소세포폐암 환자의 혈액에 존재하는 다양한 면역세포(T 세포, B 세포, NK 세포, 단핵구) 간에 PD-L1 발현이 강하게 연관되어 있음을 발견하였고, 이는 이들 세포가 동일한 PD-L1 발현 획득 과정을 공유하고 있기 때문임을 규명하였습니다. 이 과정에서 혈소판이 독특하게도 중요한 역할을 수행하는 것으로 나타났는데, 폐암 환자의 혈소판이 PD-L1을 발현하며 일부는 면역세포에 부착되어 실제로는 면역세포 자체가 PD-L1을 발현하는 것처럼 보일 수 있음을 확인하였습니다. 그러나 혈소판을 제외한 면역세포에서는 건강한 사람과 폐암 환자 간에 PD-L1 발현 차이가 관찰되지 않아, 혈액에서 관찰되는 PD-L1의 주요 공급원이 혈소판임을 입증할 수 있었습니다. 다음으로, 혈소판이 PD-L1을 획득하는 기전에 대해 규명하였습니다. 폐암 환자에서 모든 혈소판이 PD-L1을 발현하는 것이 아니라, 생성 후 하루 이내의 미성숙한 망상 혈소판에서만 PD-L1이 발현된다는 사실을 밝혀냈습니다. 흥미롭게도 이 과정은 암의 존재와 무관하며, 혈소판 생성 속도가 급증하는 다양한 상황에서 공통적으로 나타나는 현상이었습니다. 다만, 폐암이 전신에 전이될 경우 혈소판 소비 속도가 증가하여 혈소판 생성이 촉진됨에 따라 간접적으로 PD-L1 발현이 유도될 가능성이 있다고 생각됩니다. 마지막으로, 이러한 혈소판의 PD-L1 발현이 임상적으로 어떤 의미를 지니는지 분석하였습니다. 면역관문억제제 치료를 받은 비소세포폐암 환자의 baseline 혈액을 분석한 결과, 혈소판의 PD-L1 수치가 높은 환자가 면역치료에 대해 더 좋은 반응을 보임을 확인할 수 있었으며, 이는 혈소판의 PD-L1이 면역 억제 기능을 수행하고 있음을 시사합니다. 특히, 혈소판의 PD-L1과 종양 내 PD-L1이 예측하는 반응자 그룹이 서로 다르다는 점은, 혈소판에 의한 전신적 면역억제와 종양 내 PD-L1에 의한 국소적 면역억제가 서로 다른 기전으로 작용함을 의미합니다. 결론적으로, 본 연구를 통해 폐암 환자에서 혈소판의 PD-L1 발현 기전과 그 임상적 의미를 새롭게 규명할 수 있었습니다.- 이성우(전남대학교 의과대학)
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