Soluble PD‑L1 reflects cachexia status in patients with gastric cancer and is an independent prognostic marker for relapse‑free survival after radical surgery

Matsumoto,Yasunori; Sasaki,Takuma; Kano,Masayuki; Shiraishi,Tadashi; Suito,Hiroshi; Murakami,Kentaro; Toyozumi,Takeshi; Otsuka,Ryota; Kinoshita,Kazuya; Iida,Shinichiro; Morishita,Hiroki; Nishioka,Yuri; Hayano,Koichi; Kurata,Yoshihiro; Hayashi,Hideki; Matsubara,Hisahiro

doi:10.3892/mco.2023.2635

Soluble PD‑L1 reflects cachexia status in patients with gastric cancer and is an independent prognostic marker for relapse‑free survival after radical surgery

Authors:
- Yasunori Matsumoto
- Takuma Sasaki
- Masayuki Kano
- Tadashi Shiraishi
- Hiroshi Suito
- Kentaro Murakami
- Takeshi Toyozumi
- Ryota Otsuka
- Kazuya Kinoshita
- Shinichiro Iida
- Hiroki Morishita
- Yuri Nishioka
- Koichi Hayano
- Yoshihiro Kurata
- Hideki Hayashi
- Hisahiro Matsubara
View Affiliations

Affiliations: Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 2608670, Japan
Published online on: March 20, 2023 https://doi.org/10.3892/mco.2023.2635
Article Number: 39
Copyright: © Matsumoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Soluble programmed death‑ligand 1 (sPD‑L1) levels can be used as a biomarker for gastric cancer (GC). However, comprehensive information regarding the sPD‑L1 expression profiles and their association with cachexia in GC is lacking. Therefore, the present study evaluated the association between clinicopathological findings and sPD‑L1 levels in patients with GC. Serum samples were collected from patients with GC during their first visit to Department of Esophageal‑Gastro‑Intestinal Surgery, Chiba University Hospital, Chiba, Japan (January 2012‑December 2017; n=173), and sPD‑L1 levels were measured using an enzyme‑linked immunosorbent assay. Survival rates among 116 patients, excluding cases with preoperative chemotherapy or no radical procedures, were analyzed. sPD‑L1 levels were associated with factors such as neutrophil‑to‑lymphocyte ratio, hemoglobin (Hb) and albumin (Alb) levels, total cholesterol and C‑reactive protein (CRP) levels, and related to inflammation and nutrition in patients. Notably, the higher the number of applicable indicators related to cachexia (Hb <12 g/dl, Alb <3.2 g/dl, CRP >0.5 mg/dl and low body mass index) was, the higher the sPD‑L1 value was. However, the pathological stage did not significantly differ between the groups. Clinicopathologically, there was no association with tumor depth, lymph node metastasis or vascular invasion; however, patients with the intestinal type had significantly higher sPD‑L1 levels than patients with the diffuse type (P=0.032; Wilcoxon test). The overall survival did not significantly differ between the groups with low and high sPD‑L1 levels; however, among patients who received radical treatment, the relapse‑free survival was significantly worse in the high‑sPD‑L1‑level group than in the low‑sPD‑L1‑level group (P=0.025; log‑rank test). Multivariate Cox regression analysis revealed that a high sPD‑L1 concentration was a sign of poor prognosis, independent of pathological stage and cancer antigen CA19‑9 (P=0.0029). Therefore, the present findings suggest that sPD‑L1 can reflect cachexia status in patients with GC and may serve as a prognostic marker for relapse‑free survival after radical GC surgery.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
2	Baazim H, Antonio-Herrera L and Bergthaler A: The interplay of immunology and cachexia in infection and cancer. Nat Rev Immunol. 22:309–321. 2022.PubMed/NCBI View Article : Google Scholar
3	Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, et al: Definition and classification of cancer cachexia: An international consensus. Lancet Oncol. 12:489–495. 2011.PubMed/NCBI View Article : Google Scholar
4	Fukahori M, Shibata M, Hamauchi S, Kasamatsu E and Machii K: A retrospective cohort study to investigate the incidence of cancer-related weight loss during chemotherapy in gastric cancer patients. Support Care Cancer. 29:341–348. 2021.PubMed/NCBI View Article : Google Scholar
5	Namikawa T, Marui A, Yokota K, Fujieda Y, Munekage M, Uemura S, Maeda H, Kitagawa H, Kobayashi M and Hanazaki K: Frequency and prognostic impact of cachexia during drug treatment for unresectable advanced gastric cancer patients. Surg Today. 52:1560–1567. 2022.PubMed/NCBI View Article : Google Scholar
6	Morimoto K, Uchino J, Yokoi T, Kijima T, Goto Y, Nakao A, Hibino M, Takeda T, Yamaguchi H, Takumi C, et al: Impact of cancer cachexia on the therapeutic outcome of combined chemoimmunotherapy in patients with non-small cell lung cancer: A retrospective study. OncoImmunology. 10(1950411)2021.PubMed/NCBI View Article : Google Scholar
7	Nielsen C, Ohm-Laursen L, Barington T, Husby S and Lillevang ST: Alternative splice variants of the human PD-1 gene. Cell Immunol. 235:109–116. 2005.PubMed/NCBI View Article : Google Scholar
8	Finkelmeier F, Canli Ö, Tal A, Pleli T, Trojan J, Schmidt M, Kronenberger B, Zeuzem S, Piiper A, Greten FR and Waidmann O: High levels of the soluble programmed death-ligand (sPD-L1) identify hepatocellular carcinoma patients with a poor prognosis. Eur J Cancer. 59:152–159. 2016.PubMed/NCBI View Article : Google Scholar
9	Chang B, Huang T, Wei H, Shen L, Zhu D, He W, Chen Q, Zhang H, Li Y, Huang R, et al: The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 68:353–363. 2019.PubMed/NCBI View Article : Google Scholar
10	Okuma Y, Hosomi Y, Nakahara Y, Watanabe K, Sagawa Y and Homma S: High plasma levels of soluble programmed cell death ligand 1 are prognostic for reduced survival in advanced lung cancer. Lung Cancer. 104:1–6. 2017.PubMed/NCBI View Article : Google Scholar
11	Shigemori T, Toiyama Y, Okugawa Y, Yamamoto A, Yin C, Narumi A, Ichikawa T, Ide S, Shimura T, Fujikawa H, et al: Soluble PD-L1 expression in circulation as a predictive marker for recurrence and prognosis in gastric cancer: Direct comparison of the clinical burden between tissue and serum PD-L1 expression. Ann Surg Oncol. 26:876–883. 2019.PubMed/NCBI View Article : Google Scholar
12	Ito M, Oshima Y, Yajima S, Suzuki T, Nanami T, Shiratori F, Funahashi K, Nemoto T and Shimada H: Is high serum programmed death ligand 1 level a risk factor for poor survival in patients with gastric cancer? Ann Gastroenterol Surg. 2:313–318. 2018.PubMed/NCBI View Article : Google Scholar
13	Takahashi N, Iwasa S, Sasaki Y, Shoji H, Honma Y, Takashima A, Okita NT, Kato K, Hamaguchi T and Yamada Y: Serum levels of soluble programmed cell death ligand 1 as a prognostic factor on the first-line treatment of metastatic or recurrent gastric cancer. J Cancer Res Clin Oncol. 142:1727–1738. 2016.PubMed/NCBI View Article : Google Scholar
14	Park W, Bang JH, Nam AR, Jin MH, Seo H, Kim JM, Oh KS, Kim TY and Oh DY: Prognostic value of serum soluble programmed death-ligand 1 and dynamics during chemotherapy in advanced gastric cancer patients. Cancer Res Treat. 53:199–206. 2021.PubMed/NCBI View Article : Google Scholar
15	Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H and Kwon ED: Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res. 17:1915–1923. 2011.PubMed/NCBI View Article : Google Scholar
16	Tanaka H, Yoshii M, Imai T, Tamura T, Toyokawa T, Muguruma K, Hirakawa K and Ohira M: Clinical significance of coexisting histological diffuse type in stage II/III gastric cancer. Mol Clin Oncol. 15(234)2021.PubMed/NCBI View Article : Google Scholar
17	Shiraishi T, Toyozumi T, Sakata H, Murakami K, Kano M, Matsumoto Y, Yokoyama M, Okada K, Kamata T, Ryuzaki T, et al: Soluble PD-L1 concentration is proportional to the expression of PD-L1 in tissue and is associated with a poor prognosis in esophageal squamous cell carcinoma. Oncology. 100:39–47. 2022.PubMed/NCBI View Article : Google Scholar
18	Park JC, Lee YC, Kim JH, Kim YJ, Lee SK, Hyung WJ, Noh SH and Kim CB: Clinicopathological aspects and prognostic value with respect to age: An analysis of 3,362 consecutive gastric cancer patients. J Surg Oncol. 99:395–401. 2009.PubMed/NCBI View Article : Google Scholar
19	Song P, Wu L, Jiang B, Liu Z, Cao K and Guan W: Age-specific effects on the prognosis after surgery for gastric cancer: A SEER population-based analysis. Oncotarget. 7:48614–48624. 2016.PubMed/NCBI View Article : Google Scholar
20	Alshehri A, Alanezi H and Kim BS: Prognosis factors of advanced gastric cancer according to sex and age. World J Clin Cases. 8:1608–1619. 2020.PubMed/NCBI View Article : Google Scholar
21	Imai Y, Chiba T, Kondo T, Kanzaki H, Kanayama K, Ao J, Kojima R, Kusakabe Y, Nakamura M, Saito T, et al: Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer. Oncol Lett. 20:2161–2168. 2020.PubMed/NCBI View Article : Google Scholar
22	Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, et al: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 192:1027–1034. 2000.PubMed/NCBI View Article : Google Scholar
23	Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T and Minato N: Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 99:12293–12297. 2002.PubMed/NCBI View Article : Google Scholar
24	Iwai Y, Terawaki S and Honjo T: PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 17:133–144. 2005.PubMed/NCBI View Article : Google Scholar
25	Akutsu Y, Murakami K, Kano M, Toyozumi T, Matsumoto Y, Takahashi M, Otsuka R, Sekino N, Yokoyama M, Shiraishi T and Matsubara H: The concentration of programmed cell death-ligand 1 in the peripheral blood is a useful biomarker for esophageal squamous cell carcinoma. Esophagus. 15:103–108. 2018.PubMed/NCBI View Article : Google Scholar
26	Zhu Y, Zhu F, Ba H, Chen J and Bian X: Helicobacter pylori infection and PD-L1 expression in gastric cancer: A meta-analysis. Eur J Clin Invest. 53(e13880)2023.PubMed/NCBI View Article : Google Scholar
27	Oh SY, Kim S, Keam B, Kim TM, Kim DW and Heo DS: Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment. Sci Rep. 11(19712)2021.PubMed/NCBI View Article : Google Scholar
28	Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, et al: Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 560:382–386. 2018.PubMed/NCBI View Article : Google Scholar
29	Wei H, Wu F, Mao Y, Zhang Y, Leng G, Wang J, Zhang W and Wang T: Measurement of soluble PD-1 and soluble PD-L1 as well as PD-L1 and PD-1 from perioperative patients with gastric carcinoma. Jpn J Clin Oncol. 52:331–345. 2022.PubMed/NCBI View Article : Google Scholar
30	Naito T, Uchino J, Kojima T, Matano Y, Minato K, Tanaka K, Mizukami T, Atagi S, Higashiguchi T, Muro K, et al: A multicenter, open-label, single-arm study of anamorelin (ONO-7643) in patients with cancer cachexia and low body mass index. Cancer. 128:2025–2035. 2022.PubMed/NCBI View Article : Google Scholar