Predictive factors in the treatment of oral squamous cell carcinoma using PD-1/PD-L1 inhibitors

Summary

Due to immune impairment and lymphocyte enrichment of oral squamous cell carcinoma (OSCC), anti-PD-1/PD-L1 therapy is regarded as a potential treatment option. However, tumor heterogeneity, differences in the immune conditions of patients, and the interrelation between tumor cells and stromal cells within the tumor microenvironment (TME) could affect the therapeutic efficacy of immune checkpoint blockades. Therefore, to maximize the benefit of blockade PD-1/PD-L1 axis, to find an efficient predictor (the possible clinical parameters or biological factors) before treatment are of great importance. In this review, we discuss the advantages of anti-PD-1/PD-L1 therapy for OSCC patients and find three respects that are currently available in predicting curative effect. Firstly, OSCC with high PD-L1 expression evaluating by immunohistochemistry (high tumor proportion score (TPS) and combined positive score (CPS)) are considered to be suitable for anti-PD-1/PD-L1 therapy. Secondly, gene-level predictive biomarkers including high metastatic mismatch repair deficiency (dMMR) signature or enrichment of interferon-γ and PD1 signaling pathway is expected to be favorable factors. Besides, PET/CT parameters (SUVmax, MTV, TLG) are proved to be correlated with PD-L1 expression, and some newly developed immunoPET probes are enlarging the application of PET/CT in predicting therapeutic efficacy of PD-1/PD-L1 inhibitors.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. 1.

    de Vicente JC, Rodriguez-Santamarta T, Rodrigo JP, Blanco-Lorenzo V, Allonca E, Garcia-Pedrero JM (2019) PD-L1 expression in tumor cells is an independent unfavorable prognostic factor in oral squamous cell carcinoma. Cancer Epidemiol Biomark Prev 28(3):546–554. https://doi.org/10.1158/1055-9965.EPI-18-0779

    Article  Google Scholar 

  2. 2.

    Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ (2016) Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17(7):956–965. https://doi.org/10.1016/S1470-2045(16)30066-3

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867. https://doi.org/10.1056/NEJMoa1602252

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kaidar-Person O, Gil Z, Billan S (2018) Precision medicine in head and neck cancer. Drug Resist Updat 40:13–16. https://doi.org/10.1016/j.drup.2018.09.001

    Article  PubMed  Google Scholar 

  5. 5.

    Takahashi H, Sakakura K, Arisaka Y, Tokue A, Kaira K, Tada H, Higuchi T, Okamoto A, Tsushima Y, Chikamatsu K (2019) Clinical and Biological Significance of PD-L1 Expression Within the Tumor Microenvironment of Oral Squamous Cell Carcinoma. Anticancer Res 39(6):3039–3046. https://doi.org/10.21873/anticanres.13437

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Lenouvel D, Gonzalez-Moles MA, Talbaoui A, Ramos-Garcia P, Gonzalez-Ruiz L, Ruiz-Avila I, Gil-Montoya JA (2020) An update of knowledge on PD-L1 in head and neck cancers: Physiologic, prognostic and therapeutic perspectives. Oral Dis 26(3):511–526. https://doi.org/10.1111/odi.13088

    Article  PubMed  Google Scholar 

  7. 7.

    Yoshida S, Nagatsuka H, Nakano K, Kogashiwa Y, Ebihara Y, Yano M, Yasuda M (2018) Significance of PD-L1 expression in tongue cancer development. Int J Med Sci 15(14):1723–1730. https://doi.org/10.7150/ijms.27860

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, Burtness B, Busse PM, Caudell JJ, Cmelak AJ, Colevas AD, Eisele DW, Fenton M, Foote RL, Gilbert J, Haddad RI, Hicks WL, Hitchcock YJ, Jimeno A, Leizman D, Lydiatt WM, Maghami E, Mell LK, Mittal BB, Pinto HA, Ridge JA, Rocco J, Rodriguez CP, Shah JP, Weber RS, Witek M, Worden F, Yom SS, Zhen W, Burns JL, Darlow SD (2017) NCCN guidelines insights: head and neck cancers, version 2.2017. J Natl Compr Canc Netw 15(6):761–770. https://doi.org/10.6004/jnccn.2017.0101

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr, Psyrri A, Baste N, Neupane P, Bratland A, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, Gonzalez Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D, Investigators K- (2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394(10212):1915–1928. https://doi.org/10.1016/S0140-6736(19)32591-7

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Varilla V, Atienza J, Dasanu CA (2013) Immune alterations and immunotherapy prospects in head and neck cancer. Expert Opin Biol Ther 13(9):1241–1256. https://doi.org/10.1517/14712598.2013.810716

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Meehan K, Leslie C, Lucas M, Jacques A, Mirzai B, Lim J, Bulsara M, Khan Y, Wong NC, Solomon B, Sader C, Friedland P, Mir Arnau G, Semple T, Lim AM (2020) Characterization of the immune profile of oral tongue squamous cell carcinomas with advancing disease. Cancer Med 9(13):4791–4807. https://doi.org/10.1002/cam4.3106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Hirai M, Kitahara H, Kobayashi Y, Kato K, Bou-Gharios G, Nakamura H, Kawashiri S (2017) Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment. Int J Oncol 50(1):41–48. https://doi.org/10.3892/ijo.2016.3785

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Lei Y, Xie Y, Tan YS, Prince ME, Moyer JS, Nor J, Wolf GT (2016) Telltale tumor infiltrating lymphocytes (TIL) in oral, head & neck cancer. Oral Oncol 61:159–165. https://doi.org/10.1016/j.oraloncology.2016.08.003

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, Lee KW, Ganly I, Hakimi AA, Chan TA, Morris LG (2016) The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1(17):e89829. https://doi.org/10.1172/jci.insight.89829

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ, investigators K- (2019) Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393(10167):156–167. https://doi.org/10.1016/S0140-6736(18)31999-8

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Sim F, Leidner R, Bell RB (2019) Immunotherapy for head and neck cancer. Hematol Oncol Clin North Am 33(2):301–321. https://doi.org/10.1016/j.hoc.2018.12.006

    Article  PubMed  Google Scholar 

  17. 17.

    Chen DS, Mellman I (2017) Elements of cancer immunity and the cancer-immune set point. Nature 541(7637):321–330. https://doi.org/10.1038/nature21349

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L, Spranger S (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25(2):268–276. https://doi.org/10.1016/j.coi.2013.02.009

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Foy JP, Bertolus C, Michallet MC, Deneuve S, Incitti R, Bendriss-Vermare N, Albaret MA, Ortiz-Cuaran S, Thomas E, Colombe A, Py C, Gadot N, Michot JP, Fayette J, Viari A, Van den Eynde B, Goudot P, Devouassoux-Shisheboran M, Puisieux A, Caux C, Zrounba P, Lantuejoul S, Saintigny P (2017) The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Ann Oncol 28(8):1934–1941. https://doi.org/10.1093/annonc/mdx210

    Article  PubMed  Google Scholar 

  20. 20.

    Hanna GJ, Liu H, Jones RE, Bacay AF, Lizotte PH, Ivanova EV, Bittinger MA, Cavanaugh ME, Rode AJ, Schoenfeld JD, Chau NG, Haddad RI, Lorch JH, Wong KK, Uppaluri R, Hammerman PS (2017) Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck. Oral Oncol 67:61–69. https://doi.org/10.1016/j.oraloncology.2017.02.005

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Liu S, Liu D, Li J, Zhang D, Chen Q (2016) Regulatory T cells in oral squamous cell carcinoma. J Oral Pathol Med 45(9):635–639. https://doi.org/10.1111/jop.12445

    Article  PubMed  Google Scholar 

  22. 22.

    Ngiow SF, Young A, Jacquelot N, Yamazaki T, Enot D, Zitvogel L, Smyth MJ (2015) A threshold level of intratumor CD8 + T-cell PD1 expression dictates therapeutic response to anti-PD1. Cancer Res 75(18):3800–3811. https://doi.org/10.1158/0008-5472.CAN-15-1082

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Hui L, Chen Y (2015) Tumor microenvironment: Sanctuary of the devil. Cancer Lett 368(1):7–13. https://doi.org/10.1016/j.canlet.2015.07.039

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Satgunaseelan L, Gupta R, Madore J, Chia N, Lum T, Palme CE, Boyer M, Scolyer RA, Clark JR (2016) Programmed cell death-ligand 1 expression in oral squamous cell carcinoma is associated with an inflammatory phenotype. Pathology 48(6):574–580. https://doi.org/10.1016/j.pathol.2016.07.003

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Yang WF, Qin N, Song X, Jiang C, Li T, Ji P, Li Y, Ding D, Wang C, Dai J, Jin G, Chen TW, Chang YS, Ouyang DQ, Liao GQ, Hu Z, Chang KP, Su YX, Ma H (2020) Genomic signature of mismatch repair deficiency in areca nut-related oral cancer. J Dent Res. https://doi.org/10.1177/0022034520930641

    Article  PubMed  Google Scholar 

  26. 26.

    Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, Le QT, Lee NY, Leidner R, Lewis RL, Licitra L, Mehanna H, Mell LK, Raben A, Sikora AG, Uppaluri R, Whitworth F, Zandberg DP, Ferris RL (2019) The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer 7(1):184. https://doi.org/10.1186/s40425-019-0662-5

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Togo M, Yokobori T, Shimizu K, Handa T, Kaira K, Sano T, Tsukagoshi M, Higuchi T, Yokoo S, Shirabe K, Oyama T (2020) Diagnostic value of (18)F-FDG-PET to predict the tumour immune status defined by tumoural PD-L1 and CD8(+)tumour-infiltrating lymphocytes in oral squamous cell carcinoma. Br J Cancer 122(11):1686–1694. https://doi.org/10.1038/s41416-020-0820-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Tardy MP, Di Mauro I, Ebran N, Refae S, Bozec A, Benezery K, Peyrade F, Guigay J, Sudaka-Bahadoran A, Badoual C, Pedeutour F, Saada-Bouzid E (2018) Microsatellite instability associated with durable complete response to PD-L1 inhibitor in head and neck squamous cell carcinoma. Oral Oncol 80:104–107. https://doi.org/10.1016/j.oraloncology.2018.04.001

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Teng F, Meng X, Kong L, Yu J (2018) Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. Cancer Lett 414:166–173. https://doi.org/10.1016/j.canlet.2017.11.014

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Rasmussen JH, Lelkaitis G, Hakansson K, Vogelius IR, Johannesen HH, Fischer BM, Bentzen SM, Specht L, Kristensen CA, von Buchwald C, Wessel I, Friborg J (2019) Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma. Br J Cancer 120(10):1003–1006. https://doi.org/10.1038/s41416-019-0449-y

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Lim S, Phillips JB, Madeira da Silva L, Zhou M, Fodstad O, Owen LB, Tan M (2017) Interplay between immune checkpoint proteins and cellular metabolism. Cancer Res 77(6):1245–1249. https://doi.org/10.1158/0008-5472.CAN-16-1647

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Witte HM, Gebauer N, Lappohn D, Umathum VG, Riecke A, Arndt A, Steinestel K (2020) Prognostic Impact of PD-L1 Expression in Malignant Salivary Gland Tumors as Assessed by Established Scoring Criteria: Tumor Proportion Score (TPS), Combined Positivity Score (CPS), and Immune Cell (IC) Infiltrate. Cancers (Basel) 12(4). https://doi.org/10.3390/cancers12040873

  33. 33.

    Cramer JD, Burtness B, Ferris RL (2019) Immunotherapy for head and neck cancer: Recent advances and future directions. Oral Oncol 99:104460. https://doi.org/10.1016/j.oraloncology.2019.104460

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Lemery S, Keegan P, Pazdur R (2017) First FDA approval agnostic of cancer site - When a biomarker defines the indication. N Engl J Med 377(15):1409–1412. https://doi.org/10.1056/NEJMp1709968

    Article  PubMed  Google Scholar 

  35. 35.

    Vasan K, Satgunaseelan L, Anand S, Asher R, Selinger C, Low TH, Palme CE, Clark JR, Gupta R (2019) Tumour mismatch repair protein loss is associated with advanced stage in oral cavity squamous cell carcinoma. Pathology 51(7):688–695. https://doi.org/10.1016/j.pathol.2019.08.005

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Zhao P, Li L, Jiang X, Li Q (2019) Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol 12(1):54. https://doi.org/10.1186/s13045-019-0738-1

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Fumet JD, Truntzer C, Yarchoan M, Ghiringhelli F (2020) Tumour mutational burden as a biomarker for immunotherapy: Current data and emerging concepts. Eur J Cancer 131:40–50. https://doi.org/10.1016/j.ejca.2020.02.038

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Amaral-Silva GK, Martins MD, Pontes HA, Fregnani ER, Lopes MA, Fonseca FP, Vargas PA (2017) Mismatch repair system proteins in oral benign and malignant lesions. J Oral Pathol Med 46(4):241–245. https://doi.org/10.1111/jop.12484

    Article  PubMed  Google Scholar 

  39. 39.

    Li GM (2008) Mechanisms and functions of DNA mismatch repair. Cell Res 18(1):85–98. https://doi.org/10.1038/cr.2007.115

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Kok VC (2020) Current understanding of the mechanisms underlying immune evasion from PD-1/PD-L1 immune checkpoint blockade in head and neck cancer. Front Oncol 10:268. https://doi.org/10.3389/fonc.2020.00268

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Sorscher S, Lycan T (2019) Oral squamous cell cancer in a patient with Lynch syndrome. Oral Oncol 97:137–138. https://doi.org/10.1016/j.oraloncology.2019.08.014

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ (2017) A molecular portrait of microsatellite instability across multiple cancers. Nat Commun 8:15180. https://doi.org/10.1038/ncomms15180

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    De Schutter H, Spaepen M, Mc Bride WH, Nuyts S (2007) The clinical relevance of microsatellite alterations in head and neck squamous cell carcinoma: a critical review. Eur J Hum Genet 15(7):734–741. https://doi.org/10.1038/sj.ejhg.5201845

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Ryu IS, Kim JS, Roh JL, Cho KJ, Choi SH, Nam SY, Kim SY (2014) Prognostic significance of preoperative metabolic tumour volume and total lesion glycolysis measured by (18)F-FDG PET/CT in squamous cell carcinoma of the oral cavity. Eur J Nucl Med Mol Imaging 41(3):452–461. https://doi.org/10.1007/s00259-013-2571-z

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Choi WR, Oh JS, Roh JL, Kim JS, Oh I, Choi SH, Nam SY, Kim SY (2019) Metabolic tumor volume and total lesion glycolysis predict tumor progression and survival after salvage surgery for recurrent oral cavity squamous cell carcinoma. Head Neck 41(6):1846–1853. https://doi.org/10.1002/hed.25622

    Article  PubMed  Google Scholar 

  46. 46.

    Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6):1229–1241. https://doi.org/10.1016/j.cell.2015.08.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Kaira K, Higuchi T, Naruse I, Arisaka Y, Tokue A, Altan B, Suda S, Mogi A, Shimizu K, Sunaga N, Hisada T, Kitano S, Obinata H, Yokobori T, Mori K, Nishiyama M, Tsushima Y, Asao T (2018) Metabolic activity by (18)F-FDG-PET/CT is predictive of early response after nivolumab in previously treated NSCLC. Eur J Nucl Med Mol Imaging 45(1):56–66. https://doi.org/10.1007/s00259-017-3806-1

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Wei W, Rosenkrans ZT, Liu J, Huang G, Luo QY, Cai W (2020) ImmunoPET: concept, design, and applications. Chem Rev 120(8):3787–3851. https://doi.org/10.1021/acs.chemrev.9b00738

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Stutvoet TS, van der Veen EL, Kol A, Antunes IF, de Vries EFJ, Hospers GAP, de Vries EGE, de Jong S, Lub-de Hooge MN (2020) Molecular imaging of PD-L1 expression and dynamics with the adnectin-based PET tracer (18)F-BMS-986192. J Nucl Med. https://doi.org/10.2967/jnumed.119.241364

    Article  PubMed  Google Scholar 

  50. 50.

    Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok IC, Oosting SF, Schroder CP, Hiltermann TJN, van der Wekken AJ, Groen HJM, Kwee TC, Elias SG, Gietema JA, Bohorquez SS, de Crespigny A, Williams SP, Mancao C, Brouwers AH, Fine BM, de Vries EGE (2018) (89)Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med 24(12):1852–1858. https://doi.org/10.1038/s41591-018-0255-8

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank the Fundamental Research Funds for the Central Universities (14380942) for financial support.

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This work was supported by the Fundamental Research Funds for the Central Universities (14380492).

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Antian Gao contributed to data acquisition, and drafted this manuscript. Xiao Pan contributed to data curation. Zitong Lin and Xudong Yang contributed to guidance of manuscript writing, and founding acquisition. All authors gave final approval and agreed to be accountable for all aspects of the work.

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Correspondence to Xudong Yang or Zitong Lin.

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Gao, A., Pan, X., Yang, X. et al. Predictive factors in the treatment of oral squamous cell carcinoma using PD-1/PD-L1 inhibitors. Invest New Drugs (2021). https://doi.org/10.1007/s10637-021-01082-w

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Keywords

  • Oral squamous cell carcinoma
  • PD-1/PD-L1 inhibitors
  • Immunohistochemistry
  • Gene signature
  • PET-CT