We aimed to evaluate the prognostic value of natural killer (NK) cell activity for patients with HER2 + advanced gastric cancer (AGC) treated with first-line fluoropyrimidine–platinum doublet plus trastuzumab.
Forty-one patients with HER2 + AGC who received fluoropyrimidine–platinum doublet plus trastuzumab as first-line treatment were prospectively enrolled. NK cell activity was evaluated using the NK Vue®.
The median age was 63.5 years, and 31 patients (75.6%) were male. Patients with low baseline NK cell activity (≤ median, n = 21) were associated worse progression-free survival (PFS) and overall survival (OS) compared with patients with high baseline NK cell activity (> median, n = 20) with a median PFS of 4.21 vs. 9.53 months (P < 0.001), and median OS of 8.15 months vs. 17.82 months (P = 0.025), respectively. In the multivariate analysis, low baseline NK cell activity was independently associated with poor PFS (HR 4.35, P = 0.007). NK cell activity recovered to a normal range in nine patients (47.4%) with a low baseline NK cell activity (n = 19) after two cycles of treatment. The median PFS and OS among patients with recovered NK cell activity were significantly better than that among patients with persistently low NK cell activity (PFS, P = 0.038; OS, P = 0.003).
Our results demonstrated the prognostic value of baseline NK cell activity for patients with HER2 + AGC treated with fluoropyrimidine–platinum doublet plus trastuzumab. The association between treatment outcomes and dynamic changes in NK cell activity suggests that NK cell treatment may improve treatment outcomes, especially for patients with low baseline NK cell activity.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Availability of data and material
Data are available on reasonable request.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492
Wagner AD, Syn NL, Moehler M, Grothe W, Yong WP, Tai BC, Ho J, Unverzagt S (2017) Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD004064.pub4
Koo DH, Ryu MH, Ryoo BY, Seo J, Lee MY, Chang HM, Lee JL, Lee SS, Kim TW, Kang YK (2015) Improving trends in survival of patients who receive chemotherapy for metastatic or recurrent gastric cancer: 12 years of experience at a single institution. Gastric Cancer 18:346–353. https://doi.org/10.1007/s10120-014-0385-8
Koo DH, Ryoo BY, Kim HJ, Ryu MH, Lee SS, Moon JH, Chang HM, Lee JL, Kim TW, Kang YK (2011) A prognostic model in patients who receive chemotherapy for metastatic or recurrent gastric cancer: validation and comparison with previous models. Cancer Chemother Pharmacol 68:913–921. https://doi.org/10.1007/s00280-011-1561-8
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK, Investigators TT (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697. https://doi.org/10.1016/S0140-6736(10)61121-X
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J, Trial Investigators REGARD (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 383:31–39. https://doi.org/10.1016/S0140-6736(13)61719-5
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A, RAINBOW Study Group (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15:1224–1235. https://doi.org/10.1016/S1470-2045(14)70420-6
Hudis CA (2007) Trastuzumab — mechanism of action and use in clinical practice. N Engl J Med 357:39–51. https://doi.org/10.1056/NEJMra043186
Kono K, Takahashi A, Ichihara F, Sugai H, Fujii H, Matsumoto Y (2002) Impaired antibody-dependent cellular cytotoxicity mediated by herceptin in patients with gastric cancer. Cancer Res 62:5813–5817
Du Y, Wei Y (2019) Therapeutic potential of natural killer cells in gastric cancer. Front Immunol 9:3095. https://doi.org/10.3389/fimmu.2018.03095
Takeuchi H, Maehara Y, Tokunaga E, Koga T, Kakeji Y, Sugimachi K (2001) Prognostic significance of natural killer cell activity in patients with gastric carcinoma: a multivariate analysis. Am J Gastroenterol 96:574–578. https://doi.org/10.1111/j.1572-0241.2001.03535.x
Jobin G, Rodriguez-Suarez R, Betito K (2017) Association between natural killer cell activity and colorectal cancer in high-risk subjects undergoing colonoscopy. Gastroenterology 153:980–987. https://doi.org/10.1053/j.gastro.2017.06.009
Hansen TF, Nederby L, Zedan AH, Mejlholm I, Henriksen JR, Steffensen KD, Thomsen CB, Raunkilde L, Jensen LH, Jakobsen A (2019) Correlation between natural killer cell activity and treatment effect in patients with disseminated cancer. Transl Oncol 12:968–972. https://doi.org/10.1016/j.tranon.2019.04.002
Kondo E, Koda K, Takiguchi N, Oda K, Seike K, Ishizuka M, Miyazaki M (2003) Preoperative natural killer cell activity as a prognostic factor for distant metastasis following surgery for colon cancer. Dig Surg 20:445–451. https://doi.org/10.1159/000072714
Liljefors M, Nilsson B, Hjelm Skog AL, Ragnhammar P, Mellstedt H, Frödin JE (2003) Natural killer (NK) cell function is a strong prognostic factor in colorectal carcinoma patients treated with the monoclonal antibody 17–1A. Int J Cancer 105:717–723. https://doi.org/10.1002/ijc.11139
Cifaldi L, Locatelli F, Marasco E, Moretta L, Pistoia V (2017) Boosting natural killer cell-based immunotherapy with anticancer drugs: a perspective. Trends Mol Med 23:1156–1175. https://doi.org/10.1016/j.molmed.2017.10.002
Shi L, Lin H, Li G, Sun Y, Shen J, Xu J, Lin C, Yeh S, Cai X, Chang C (2016) Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals. Cancer Lett 373:45–56. https://doi.org/10.1016/j.canlet.2016.01.017
Tian X, Wei F, Wang L, Yu W, Zhang N, Zhang X, Han Y, Yu J, Ren X (2017) Herceptin enhances the antitumor effect of natural killer cells on breast cancer cells expressing human epidermal growth factor receptor-2. Front Immunol 8:1426. https://doi.org/10.3389/fimmu.2017.01426
Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C, Cabaret V, Fermeaux V, Bertheau P, Garnier J, Jeannin JF, Coudert B (2006) Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer 94:259–267. https://doi.org/10.1038/sj.bjc.6602930
Ménard C, Blay JY, Borg C, Michiels S, Ghiringhelli F, Robert C, Nonn C, Chaput N, Taïeb J, Delahaye NF, Flament C, Emile JF, Le Cesne A, Zitvogel L (2009) Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res 69:3563–3569. https://doi.org/10.1158/0008-5472.CAN-08-3807
Shimasaki N, Jain A, Campana D (2020) NK cells for cancer immunotherapy. Nat Rev Drug Discov 19:200–218. https://doi.org/10.1038/s41573-019-0052-1
Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, Wang Z, Wu Q, Peng H, Wei H, Sun R, Tian Z (2018) Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol 19:723–732. https://doi.org/10.1038/s41590-018-0132-0
André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Bléry M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E (2018) Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175(1731–43):e13. https://doi.org/10.1016/j.cell.2018.10.014
Ishikawa T, Okayama T, Sakamoto N, Ideno M, Oka K, Enoki T, Mineno J, Yoshida N, Katada K, Kamada K, Uchiyama K, Handa O, Takagi T, Konishi H, Kokura S, Uno K, Naito Y, Itoh Y (2018) Phase I clinical trial of adoptive transfer of expanded natural killer cells in combination with IgG1 antibody in patients with gastric or colorectal cancer. Int J Cancer 142:2599–2609. https://doi.org/10.1002/ijc.31285
Lin M, Luo H, Liang S, Chen J, Liu A, Niu L, Jiang Y (2020) Pembrolizumab plus allogeneic NK cells in advanced non-small cell lung cancer patients. J Clin Invest 130:2560–2569. https://doi.org/10.1172/JCI132712
Rha SY, Lee CK, Kim HS, Kang B, Jung M, Kyun W, Koo DH, Shin SJ, Jeung HC, Zang DY, Chung HC (2020) Targeting HER2 in combination with anti-PD-1 and chemotherapy confers a significant tumor shrinkage of gastric cancer: a multi-institutional phase Ib/II trial of first-line triplet regimen (pembrolizumab, trastuzumab, chemotherapy) for HER2-positive advanced gastric cancer (AGC). J Clin Oncol 38:3081. https://doi.org/10.1200/JCO.2020.38.15_suppl.3081
Stabile H, Fionda C, Gismondi A, Santoni A (2017) Role of distinct natural killer cell subsets in anticancer response. Front Immunol 8:293. https://doi.org/10.3389/fimmu.2017.00293
Melaiu O, Lucarini V, Cifaldi L, Fruci D (2019) Influence of the tumor microenvironment on NK cell function in solid tumors. Front Immunol 10:3038. https://doi.org/10.3389/fimmu.2019.03038
Li T, Zhang Q, Jiang Y, Yu J, Hu Y, Mou T, Chen G, Li G (2016) Gastric cancer cells inhibit natural killer cell proliferation and induce apoptosis via prostaglandin E2. Oncoimmunology 5:e1069936. https://doi.org/10.1080/2162402X.2015.1069936
Conflict of interest
The authors declare that they do not have any conflict of interest.
This study was approved by the ethics committee, and all patients provided written informed consent.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Hyungwoo Cho and Min-Hee Ryu are Co-first authors.
Below is the link to the electronic supplementary material.
About this article
Cite this article
Cho, H., Ryu, MH., Lee, H.E. et al. Prognostic value of natural killer cell activity for patients with HER2 + advanced gastric cancer treated with first-line fluoropyrimidine–platinum doublet plus trastuzumab. Cancer Immunol Immunother 71, 829–838 (2022). https://doi.org/10.1007/s00262-021-03035-x