Cancer Research on Prevention and Treatment    2022, Vol. 49 Issue (07) : 721-726     DOI: 10.3971/j.issn.1000-8578.2022.21.1281
Current Status and Prospects of Immunotherapy for Osteosarcoma
WU Wei, JING Doudou, CAO Li, PU Feifei, SHAO Zengwu
Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Download: PDF(4308 KB)   ( 209 )   HTML ()
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract Osteosarcoma is a malignant tumor with extreme invasiveness and metastasis as well as dismal prognosis. It is critical to rapidly find a unique therapy strategy capable of significantly improving the prognosis of osteosarcoma. Tumor immunotherapy has the potential to reawaken the immune system, restart and sustain the tumor-immune cycle in the body, resulting in the death of tumor cells. CD8+ CTL, CD4+ T cells, NK cells and NKT cells all play critical roles in tumor immunity, while humoral immunity may not only inhibit tumor growth but also enhance it. Researchers have devised various strategies to boost the immune system in recent years based on tumor immune response studies. This paper highlights and examines osteosarcoma immunotherapy from two perspectives: (1) boosting the response of patient’s own immune system to the tumor; (2) exogenously improving the patient’s immunological function.
Keywords Osteosarcoma      Tumor immune escape      Immunotherapy     
ZTFLH:  R738.1  
Fund:National Natural Science Funding of China (No. 81904231); China Postdoctoral Science Foundation (No. 2020M672369)
Issue Date: 14 July 2022
 Cite this article:   
WU Wei,JING Doudou,CAO Li, et al. Current Status and Prospects of Immunotherapy for Osteosarcoma[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 721-726.
E-mail this article
E-mail Alert
Articles by authors
WU Wei
JING Doudou
PU Feifei
SHAO Zengwu
[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018[J]. CA
Cancer J Clin, 2018, 68(1): 7-30.
[2] Chen C, Xie L, Ren T, et al. Immunotherapy for osteosarcoma:
Fundamental mechanism, rationale, and recent breakthroughs[J].
Cancer Lett, 2021, 500: 1-10.
[3] Choi JH, Ro JY. The 2020 WHO Classification of Tumors of Bone:
An Updated Review[J]. Adv Anat Pathol, 2021, 28(3): 119-138.
[4] Meyers PA, Healey JH, Chou AJ, et al. Addition of pamidronate to
chemotherapy for the treatment of osteosarcoma[J]. Cancer, 2011,
117(8): 1736-1744.
[5] Haworth KB, Leddon JL, Chen CY, et al. Going back to class
I: MHC and immunotherapies for childhood cancer[J]. Pediatr
Blood Cancer, 2015, 62(4): 571-576.
[6] Subleski JJ, Wiltrout RH, Weiss JM. Application of tissuespecific
NK and NKT cell activity for tumor immunotherapy[J]. J
Autoimmun, 33(3-4): 275-281.
[7] Tan TT, Coussens LM. Humoral immunity, inflammation and
cancer[J]. Curr Opin Immunol, 2007, 19(2): 209-216.
[8] Gu Y, Liu Y, Fu L, et al. Tumor-educated B cells selectively
promote breast cancer lymph node metastasis by HSPA4-targeting
IgG[J]. Nat Med, 2019, 25(2): 312-322.
[9] Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of
anti-PD-L1 antibody in patients with advanced cancer[J]. N Engl
J Med, 2012, 366(26): 2455-2465.
[10] Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting:
integrating immunity’s roles in cancer suppression and
promotion[J]. Science, 2011, 331(6024): 1565-1570.
[11] Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined
Nivolumab and Ipilimumab or Monotherapy in Untreated
Melanoma[J]. N Engl J Med, 2015, 373(1): 23-34.
[12] Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade
in Resectable Lung Cancer[J]. N Engl J Med, 2018, 378(21):
[13] Lussier DM, O’Neill L, Nieves LM, et al. Enhanced T-cell
immunity to osteosarcoma through antibody blockade of PD-1/
PD-L1 interactions[J]. J Immunother, 2015, 38(3): 96-106.
[14] Liu X, He S, Wu H, et al. Blocking the PD-1/PD-L1 axis enhanced
cisplatin chemotherapy in osteosarcoma in vitro and in vivo[J].
Environ Health Prev Med, 2019, 24(1): 79.
[15] Le Cesne A, Marec-Berard P, Blay JY, et al. Programmed cell
death 1 (PD-1) targeting in patients with advanced osteosarcomas:
results from the PEMBROSARC study[J]. Eur J Cancer, 2019,
119: 151-157.
[16] Xie L, Xu J, Sun X, et al. Apatinib plus camrelizumab (anti-
PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO)
progressing after chemotherapy: a single-arm, open-label, phase 2
trial[J]. J Immunother Cancer, 2020, 8(1): e000798.
[17] Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in
advanced soft-tissue sarcoma and bone sarcoma (SARC028): a
multicentre, two-cohort, single-arm, open-label, phase 2 trial[J].
Lancet Oncol, 2017, 18(11): 1493-1501.
[18] Shen JK, Cote GM, Choy E, et al. Programmed cell death ligand 1
expr‍ession in osteosarcoma[J]. Cancer Immunol Res, 2014, 2(7):
[19] Callahan MK, Postow MA, Wolchok JD. CTLA-4 and PD-1
Pathway Blockade: Combinations in the Clinic[J]. Front Oncol,
2014, 4: 385.
[20] Hingorani P, Maas ML, Gustafson MP, et al. Increased CTLA-4(+)
T cells and an increased ratio of monocytes with loss of class
Ⅱ (CD14(+) HLA-DR(lo/neg)) found in aggressive pediatric
sarcoma patients[J]. J Immunother Cancer, 2015, 3: 35.
[21] Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy
in patients with pretreated advanced melanoma: a randomised,
double-blind, multicentre, phase 2, dose-ranging study[J]. Lancet

Oncol, 2010, 11(2): 155-164.

[22] Merchant MS, Wright M, Baird K, et al. Phase I Clinical Trial of
Ipilimumab in Pediatric Patients with Advanced Solid Tumors[J].
Clin Cancer Res, 2016, 22(6): 1364-1370.
[23] Lussier DM, Johnson JL, Hingorani P, et al. Combination
immunotherapy with α-CTLA-4 and α-PD-L1 antibody blockade
prevents immune escape and leads to complete control of
metastatic osteosarcoma[J]. J Immunother Cancer, 2015, 3: 21.
[24] Roden R, Wu TC. How will HPV vaccines affect cervical
cancer?[J]. Nat Rev Cancer, 2006, 6(10): 753-763.
[25] Dyson KA, Stover BD, Grippin A, et al. Emerging trends in
immunotherapy for pediatric sarcomas[J]. J Hematol Oncol, 2019,
12(1): 78.
[26] Mackall CL, Rhee EH, Read EJ, et al. A pilot study of
consolidative immunotherapy in patients with high-risk pediatric
sarcomas[J]. Clin Cancer Res 2008, 14(15): 4850-4858.
[27] Himoudi N, Wallace R, Parsley KL, et al. Lack of T-cell responses
following autologous tumour lysate pulsed dendritic cell
vaccination, in patients with relapsed osteosarcoma[J]. Clin Transl
Oncol, 2012, 14(4): 271-279.
[28] Miwa S, Nishida H, Tanzawa Y, et al. Phase 1/2 study of
immunotherapy with dendritic cells pulsed with autologous tumor
lysate in patients with refractory bone and soft tissue sarcoma[J].
Cancer, 2017, 123(9): 1576-1584.
[29] Wu T, Dai Y. Tumor microenvironment and therapeutic
response[J]. Cancer Lett, 2017, 387: 61-68.
[30] Qian BZ, Pollard JW. Macrophage diversity enhances tumor
progression and metastasis[J]. Cell, 2010, 141(1): 39-51.
[31] Heymann MF, Lézot F, Heymann D. The contribution of immune
infiltrates and the local microenvironment in the pathogenesis of
osteosarcoma[J]. Cell Immunol, 2019, 343: 103711.
[32] Pu F, Chen F, Zhang Z, et al. Information Transfer and
Biological Significance of Neoplastic Exosomes in the Tumor
Microenvironment of Osteosarcoma[J]. Onco Targets Ther, 2020,
13: 8931-8940.
[33] Wedekind MF, Wagner LM, Cripe TP. Immunotherapy for
osteosarcoma: Where do we go from here?[J]. Pediatr Blood
Cancer, 2018, 65(9): e27227.
[34] Woo SR, Corrales L, Gajewski TF. Innate immune recognition of
cancer[J]. Ann Rev Immunol, 2015, 33: 445-474.
[35] Wang Z, Wang Z, Li B, et al. Innate Immune Cells: A Potential and
Promising Cell Population for Treating Osteosarcoma[J]. Front
Immunol, 2019, 10: 1114.
[36] Pu F, Chen F, Liu J, et al. Immune Regulation of the cGAS-STING
Signaling Pathway in the Tumor Microenvironment and Its
Clinical Application[J]. Onco Targets Ther, 2021, 14: 1501-1516.
[37] Li A, Yi M, Qin S, et al. Activating cGAS-STING pathway for
the optimal effect of cancer immunotherapy[J]. J Hematol Oncol,
2019, 12(1): 35.
[38] Fuertes MB, Woo SR, Burnett B, et al. Type I interferon response
and innate immune sensing of cancer[J]. Trends Immunol, 2013,
34(2): 67-73.
[39] Jing W, McAllister D, Vonderhaar EP, et al. STING agonist
inflames the pancreatic cancer immune microenvironment and
reduces tumor burden in mouse models[J]. J Immunother Cancer,
2019, 7(1): 115.
[40] Ghaffari A, Peterson N, Khalaj K, et al. STING agonist therapy in
combination with PD-1 immune checkpoint blockade enhances
response to carboplatin chemotherapy in high-grade serous
ovarian cancer[J]. Br J Cancer, 2018, 119(4): 440-449.
[41] Jaspers JE, Brentjens RJ. Development of CAR T cells designed to
improve antitumor efficacy and safety[J]. Pharmacol Ther, 2017,
178: 83-91.
[42] Folkert IW, Devalaraja S, Linette GP, et al. Primary Bone Tumors:
Challenges and Opportunities for CAR-T Therapies[J]. J Bone
Miner Res, 2019, 34(10): 1780-1788.
[43] Guedan S, Calderon H, Posey AD Jr, et al. Engineering and
Design of Chimeric Antigen Receptors[J]. Mol Ther Methods Clin
Dev, 2019, 12: 145-156.
[44] Feinberg D, Paul B, Kang Y. The promise of chimeric antigen
receptor (CAR) T cell therapy in multiple myeloma[J]. Cell
Immunol, 2019, 345: 103964.
[45] Pan J, Niu Q, Deng B, et al. CD22 CAR T-cell therapy in
refractory or relapsed B acute lymphoblastic leukemia[J].
Leukemia, 2019, 33(12): 2854-2866.
[46] Pehlivan KC, Duncan BB, Lee DW. CAR-T Cell Therapy for
Acute Lymphoblastic Leukemia: Transforming the Treatment of
Relapsed and Refractory Disease[J]. Curr Hematol Malig Rep,
2018, 13(5): 396-406.
[47] Potter JW, Jones KB, Barrott JJ. Sarcoma-The standard-bearer in
cancer discovery[J]. Crit Rev Oncol Hematol, 2018, 126: 1-5.
[48] Majzner RG, Theruvath JL, Nellan A, et al. CAR T Cells Targeting
B7-H3, a Pan-Cancer Antigen, Demonstrate Potent Preclinical
Activity Against Pediatric Solid Tumors and Brain Tumors[J].
Clin Cancer Res, 2019, 25(8): 2560-2574.
[49] Théoleyre S, Mori K, Cherrier B, et al. Phenotypic and functional
analysis of lymphocytes infiltrating osteolytic tumors: use as a
possible therapeutic approach of osteosarcoma[J]. BMC Cancer,
2005, 5: 123.
[50] Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients
with metastatic melanoma with autologous tumor-infiltrating
lymphocytes and interleukin 2[J]. J Nat Cancer Inst, 1994, 86(15):
[51] Tang H, Wang Y, Chlewicki LK, et al. Facilitating T Cell
Infiltration in Tumor Microenvironment Overcomes Resistance to
PD-L1 Blockade[J]. Cancer Cell, 2016, 30(3): 500.
[52] Sierro SR, Donda A, Perret R, et al. Combination of lentivector
immunization and low-dose chemotherapy or PD-1/PD-L1
blocking primes self-reactive T cells and induces anti-tumor
immunity[J]. Eur J Immunol, 2011, 41(8): 2217-2228.
[53] Kansara M, Teng MW, Smyth MJ, et al. Translational biology of
osteosarcoma[J]. Nat Rev Cancer, 2014, 14(11): 722-735.
[54] Kovac M, Blattmann C, Ribi S, et al. Exome sequencing of
osteosarcoma reveals mutation signatures reminiscent of BRCA
deficiency[J]. Nat Commun, 2015, 6: 8940.

Related articles from Frontiers Journals
[1] YANG Junyuan, CAI Hongbing. Countermeasures and Mechanisms of Drug Resistance in Immunotherapy for Cervical Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(09): 886-892.
[2] YIN Zhucheng, LIANG Xinjun. Research Progress on Combined Immunotherapy for Microsatellite Stable Colorectal Cancer#br#[J]. Cancer Research on Prevention and Treatment, 2022, 49(09): 977-981.
[3] CAO Guangwen. Theoretical Update of Cancer Evo-Dev and Its Role in Targeted Immunotherapy for Hepatocellular Carcinoma[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 747-755.
[4] KANG Yikun, YUAN Peng. Advances in Treatment of Triple Negative Breast Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 812-819.
[5] YIN Zhucheng, LIANG Xinjun. Research Progress on Hyperthermia and Anti-Tumor Immunity[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 827-831.
[6] XIA Siyu, ZHAO Zitong, LI Li. Correlation Between STK11 Gene Mutation and Immunotherapy of Non-small Cell Lung Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(08): 850-854.
[7] CHEN Weichang, SHI Tongguo, ZHU Jinghan, SUN Linqing, LI Juntao. Progress on Immunotherapy of Gastrointestinal Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 639-643.
[8] JIN Tongtong, ZHOU Chuan, WANG Chao, DA Zijian, ZHOU Fenghai, . Research Hotspots and Frontiers of Immunotherapy for Prostate Cancer: A Visual Analysis[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 667-674.
[9] CHEN Bojin, HU Xingyi, ZHAO Jingwen, ZHENG Aihong. Current Status of Immunotherapy in Neoadjuvant Therapy for Gastric Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(07): 727-732.
[10] ZHANG Jianning, LIU Congwei. Progress of Novel Treatment Options for Glioma[J]. Cancer Research on Prevention and Treatment, 2022, 49(06): 505-513.
[11] SUN Junzhao, CHENG Gang, ZHANG Jianning. Advances in Treatment of Brain Metastasis from Lung Cancer[J]. Cancer Research on Prevention and Treatment, 2022, 49(06): 522-527.
[12] ZHANG Yu, HE Kunyu, FENG Shiyu. Current Progress in Treatment of Glioma[J]. Cancer Research on Prevention and Treatment, 2022, 49(06): 528-534.
[13] LI Yuxin, JIN Feng, . Immune Checkpoint PD-1-based Mechanisms of Tumor Immune Resistance and Strategies for Re-treatment After Drug Resistance[J]. Cancer Research on Prevention and Treatment, 2022, 49(06): 546-551.
[14] HOU Jian, WANG Junying. Research Progress of Immune Microenvironment in Multiple Myeloma[J]. Cancer Research on Prevention and Treatment, 2022, 49(05): 375-378.
[15] WEN Zhongchi, LIU Tuozhou, HE Hongbo, ZHANG Can, LIU Yupeng, LIAO Zhan, ZENG Liyi. Effect of IGF1Rβ Subunit Mutants on Proliferation, Migration and Apoptosis of Human Osteosarcoma Cells[J]. Cancer Research on Prevention and Treatment, 2022, 49(05): 390-395.
Full text