Immune checkpoint inhibitors: recent progress and potential biomarkers

다국어 초록 (Multilingual Abstract)

Cancer growth and progression are associated with immune suppression. Cancer cells have the ability to activate different immune checkpoint pathways that harbor immunosuppressive functions. Monoclonal antibodies that target immune checkpoints provided an immense breakthrough in cancer therapeutics. Among the immune checkpoint inhibitors, PD-1/PD-L1 and CTLA-4 inhibitors showed promising therapeutic outcomes, and some have been approved for certain cancer treatments, while others are under clinical trials. Recent reports have shown that patients with various malignancies benefit from immune checkpoint inhibitor treatment. However, mainstream initiation of immune checkpoint therapy to treat cancers is obstructed by the low response rate and immune-related adverse events in some cancer patients. This has given rise to the need for developing sets of biomarkers that predict the response to immune checkpoint blockade and immune-related adverse events. In this review, we discuss different predictive biomarkers for anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors, including immune cells, PD-L1 overexpression, neoantigens, and genetic and epigenetic signatures. Potential approaches for further developing highly reliable predictive biomarkers should facilitate patient selection for and decision-making related to immune checkpoint inhibitor-based therapies.

참고문헌 (Reference)

1 Cheng, W., "Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy" 7 : 2-, 2018

2 Galon, J., "Type, density, and location of immune cells within human colorectal tumors predict clinical outcome" 313 : 1960-, 2006

3 Balatoni, T., "Tumor-infiltrating immune cells as potential biomarkers predicting response to treatment and survival in patients with metastatic melanoma receiving ipilimumab therapy" 67 : 141-151, 2018

4 Daud, A. I., "Tumor immune profiling predicts response to anti–PD-1therapy in human melanoma" 126 : 3447-3452, 2016

5 Toor, S. M., "Therapeutic prospects of targeting myeloid-derived suppressor cells and immune checkpoints in cancer" 96 : 888-897, 2018

6 Mongroo, P. S., "The role of the miR-200 family in epithelialmesenchymal transition" 10 : 219-222, 2010

7 Aguiar, P. N., "The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis" 8 : 479-488, 2016

8 Korpal, M., "The miR-200 family inhibits epithelialmesenchymal transition and cancer cell migration by direct targeting of Ecadherin transcriptional repressors ZEB1 and ZEB2" 283 : 14910-14914, 2008

9 Noman, M. Z., "The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1and miR-200" 6 : e1263412-, 2017

10 Wu, S. P., "Stromal PD-L1 positive regulatory T cells and PD-1 positive CD8-positive T cells define the response of different subsets of non-small cell lung cancer to PD-1/PD-L1 blockade immunotherapy" 13 : 521-532, 2018

11 Sudo, K., "Serum microRNAs to predict the response to nivolumab in patients with esophageal squamous cell carcinoma" 35 : e14511-e14511, 2017

12 Geng, Y., "Prognostic role of tumor-infiltrating lymphocytes in lung cancer:A meta-analysis" 37 : 1560-1571, 2015

13 Manola, J., "Prognostic factors inmetastatic melanoma: A pooled analysis of eastern cooperative oncology group trials" 18 : 3782-3793, 2000

14 Gibney, G. T., "Predictive biomarkers for checkpoint inhibitor-based immunotherapy" 17 : e542-e551, 2016

15 Wistuba-Hamprecht, K., "Peripheral CD8 effector memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients" 73 : 61-70, 2017

16 Reck, M., "Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer" 375 : 1823-1833, 2016

17 Garon, E. B., "Pembrolizumab for the treatment of non–small-cell lung cancer" 372 : 2018-2028, 2015

18 Budczies, J., "Pan-cancer analysis of copy number changes in programmed death-ligand 1 (PD-L1, CD274) - associations with gene expression, mutational load, and survival" 55 : 626-639, 2016

19 Cortez, M. A., "PD-L1 regulation by p53 via miR-34" 108 : djv303-, 2016

20 Guibert, N., "PD-L1 expression in circulating tumor cells of advanced nonsmall cell lung cancer patients treated with nivolumab" 120 : 108-112, 2018

21 Patel, S. P., "PD-L1 expression as a predictive biomarker in cancer immunotherapy" 14 : 847-, 2015

22 Xu-Monette, Z. Y., "PD-1 expression and clinical PD-1blockade in B-cell lymphomas" 131 : 68-83, 2018

23 Tumeh, P. C., "PD-1 blockade induces responses by inhibiting adaptive immune resistance" 515 : 568-, 2014

24 Le, D. T., "PD-1 blockade in tumors with mismatch-repair deficiency" 372 : 2509-2520, 2015

25 Ansell, S. M., "PD-1 Blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma" 372 : 311-319, 2014

26 Zappasodi, R., "Non-conventional inhibitory CD4+Foxp3−PD-1hi T cells as a biomarker of immune checkpoint blockade activity" 33 : 1017-1032, 2018

27 Borghaei, H., "Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer" 373 : 1627-1639, 2015

28 Huber, M. A., "NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression" 114 : 569-581, 2004

29 Zaretsky, J. M., "Mutations associated with acquired resistance to PD-1blockade in melanoma" 375 : 819-829, 2016

30 Rizvi, N. A., "Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer" 348 : 124-, 2015

31 Le, D. T., "Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade" 357 : 409-413, 2017

32 Li, X., "MicroRNAs: novel immunotherapeutic targets in colorectal carcinoma" 22 : 5317-5331, 2016

33 Jenkins, R. W., "Mechanisms of resistance to immune checkpoint inhibitors" 118 : 9-16, 2018

34 Topalian, S. L., "Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy" 16 : 275-, 2016

35 Van Allen, E. M., "Long-term benefit of PD-L1 blockade in lung cancer associated with JAK3 activation" 3 : 855-, 2015

36 Kelderman, S., "Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma" 63 : 449-458, 2014

37 Loi, S., "LBA13 relationship between tumor infiltrating lymphocyte (TIL)levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086" 28 : mdx440.005-mdx440.005, 2017

38 de Coaña, Y. P., "Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma" 8 : 21539-21553, 2017

39 Robert, C., "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma" 364 : 2517-2526, 2011

40 Martens, A., "Increases in absolute lymphocytes and circulating CD4(+)and CD8(+) T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab" 22 : 4848-4858, 2016

41 Tang, D. N., "Increased frequency of ICOS(+) CD4 T-cells as a pharmacodynamic biomarker for anti-CTLA-4 therapy" 1 : 229-234, 2013

42 Hodi, F. S., "Improved survivalwith ipilimumab in patients with metastatic melanoma" 363 : 711-723, 2010

43 Simeone, E., "Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma" 63 : 675-683, 2014

44 Hodi, F. S., "Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients" 105 : 3005-3010, 2008

45 Postow, M. A., "Immune-related adverse events associated with immune checkpoint blockade" 378 : 158-168, 2018

46 Gnjatic, S., "Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy" 5 : 44-, 2017

47 Krieg, C., "High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy" 24 : 144-, 2018

48 Cogdill, A. P., "Hallmarks of response to immune checkpoint blockade" 117 : 1-7, 2017

49 Snyder, A., "Genetic basis for clinical response to CTLA-4 blockade in melanoma" 371 : 2189-2199, 2014

50 Feng, Y., "Exposure–response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma" 19 : 3977-, 2013

51 Anagnostou, V., "Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer" 7 : 264-276, 2017

52 Wright, J., "Epigenetics: reversible tags" 498 : S10-S11, 2013

53 Marwitz, S., "Epigenetic modifications of the immune-checkpoint genes CTLA4 and PDCD1 in non-small cell lung cancer results in increased expression" 9 : 51-, 2017

54 Chen, D. S., "Elements of cancer immunity and the cancer–immune set point" 541 : 321-, 2017

55 Pagès, F., "Effector memory T cells, early metastasis, and survival in colorectal cancer" 353 : 2654-2666, 2005

56 Subrahmanyam, P. B., "Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients" 6 : 18-, 2018

57 Green, M. R., "Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders:Implications for targeted therapy" 18 : 1611-, 2012

58 Larkin, J., "Combined nivolumab and ipilimumab or monotherapy in untreated melanoma" 373 : 23-34, 2015

59 McGranahan, N., "Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade" 351 : 1463-1469, 2016

60 Inoue, Y., "Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer" 7 : 32113-32128, 2016

61 Teng, M. W., "Classifying cancers based on T-cell infiltration and PD-L1" 75 : 2139-2145, 2015

62 Polk, A., "Checkpoint inhibitors in breast cancer: Current status" 63 : 122-134, 2013

63 Croce, C. M., "Causes and consequences of microRNA dysregulation in cancer" 10 : 704-714, 2009

64 Quezada, S. A., "CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells" 116 : 1935-1945, 2006

65 Liakou, C. I., "CTLA-4 blockade increases IFNγ-producing CD4(+)ICOS(hi)cells to shift the ratio of effector to regulatory T cells in cancer patients" 105 : 14987-14992, 2008

66 Chen, H., "CD4 T cells require ICOS-mediated PI3K-signaling to increase Tbet expression in the setting of anti-CTLA-4 therapy" 2 : 167-176, 2014

67 Cesano, A., "Bringing the next generation of immuno-oncology biomarkers to the clinic" 6 : 14-, 2018

68 Maleki Vareki, S., "Biomarkers of response to PD-1/PD-L1inhibition" 116 : 116-124, 2017

69 Buder-Bakhaya, K., "Biomarkers for clinical benefit of immune checkpoint inhibitor treatment—a review from the melanoma perspective and beyond" 9 : 1474-, 2018

70 Martens, A., "Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab" 22 : 2908-, 2016

71 Schmid, P., "Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses" 77 : 2986-, 2017

72 Chen, H., "Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues" 106 : 2729-, 2009

73 Angulo, G. D., "Absolute lymphocyte count is a novel prognostic indicator in ALL and AML" 112 : 407-415, 2008

74 Thommen, D. S., "A transcriptionally and functionally distinct PD-1+CD8+T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade" 24 : 994-1004, 2018

75 Ascierto, M. L., "A signature of immune function genes associated with recurrence-free survival in breast cancer patients" 131 : 871-880, 2012

76 Hamid, O., "A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma" 9 : 204-204, 2011