Top

Published in:

Open Access 01-10-2020 | Colorectal Cancer | Original Article

Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer

Authors: Reem Saleh, Rowaida Z. Taha, Salman M. Toor, Varun Sasidharan Nair, Khaled Murshed, Mahwish Khawar, Mahmood Al-Dhaheri, Mahir Abdulla Petkar, Mohamed Abu Nada, Eyad Elkord

Published in: Cancer Immunology, Immunotherapy | Issue 10/2020

Abstract

Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.

Available only for authorised users

Xia A, Zhang Y, Xu J, Yin T, Lu XJ (2019) T cell dysfunction in cancer immunity and immunotherapy. Front Immunol 10:1719. https://doi.org/10.3389/fimmu.2019.01719CrossRefPubMedPubMedCentral

Saleh R, Elkord E (2019) Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett 457:168–179. https://doi.org/10.1016/j.canlet.2019.05.003CrossRefPubMed

Saleh R, Elkord E (2019) Acquired resistance to cancer immunotherapy: Role of tumor-mediated immunosuppression. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2019.07.017CrossRefPubMed

Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S (2019) Mechanisms of resistance to immune checkpoint blockade: Why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book 39:147–164. https://doi.org/10.1200/EDBK_240837CrossRefPubMed

Easwaran H, Tsai HC, Baylin SB (2014) Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 54(5):716–727. https://doi.org/10.1016/j.molcel.2014.05.015CrossRefPubMedPubMedCentral

Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP, Schietinger A, Schumacher TN, Schwartzberg PL, Sharpe AH, Speiser DE, Wherry EJ, Youngblood BA, Zehn D (2019) Defining 'T cell exhaustion'. Nat Rev Immunol 19(11):665–674. https://doi.org/10.1038/s41577-019-0221-9CrossRefPubMedPubMedCentral

Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15(8):486–499. https://doi.org/10.1038/nri3862CrossRefPubMedPubMedCentral

Thommen DS, Schumacher TN (2018) T cell dysfunction in cancer. Cancer Cell 33(4):547–562. https://doi.org/10.1016/j.ccell.2018.03.012CrossRef

Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE, Attanasio J, Yan P, George SM, Bengsch B, Staupe RP, Donahue G, Xu W, Amaravadi RK, Xu X, Karakousis GC, Mitchell TC, Schuchter LM, Kaye J, Berger SL, Wherry EJ (2019) TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571(7764):211–218. https://doi.org/10.1038/s41586-019-1325-xCrossRefPubMedPubMedCentral

10.

Li L, Wan S, Tao K, Wang G, Zhao E (2016) KLRG1 restricts memory T cell antitumor immunity. Oncotarget 7(38):61670–61678. https://doi.org/10.18632/oncotarget.11430CrossRefPubMedPubMedCentral

11.

Agresta L, Hoebe KHN, Janssen EM (2018) The emerging role of CD244 signaling in immune cells of the tumor microenvironment. Front Immunol 9:2809. https://doi.org/10.3389/fimmu.2018.02809CrossRefPubMedPubMedCentral

12.

Paulos CM, June CH (2010) Putting the brakes on BTLA in T cell-mediated cancer immunotherapy. J Clin Invest 120(1):76–80. https://doi.org/10.1172/JCI41811CrossRefPubMed

13.

Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R, Youngblood B, Zehn D (2019) TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571(7764):265–269. https://doi.org/10.1038/s41586-019-1326-9CrossRefPubMed

14.

Seo H, Chen J, Gonzalez-Avalos E, Samaniego-Castruita D, Das A, Wang YH, Lopez-Moyado IF, Georges RO, Zhang W, Onodera A, Wu CJ, Lu LF, Hogan PG, Bhandoola A, Rao A (2019) TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8(+) T cell exhaustion. Proc Natl Acad Sci U S A 116(25):12410–12415. https://doi.org/10.1073/pnas.1905675116CrossRefPubMedPubMedCentral

15.

Chen X, Sun K, Jiao S, Cai N, Zhao X, Zou H, Xie Y, Wang Z, Zhong M, Wei L (2014) High levels of SIRT1 expression enhance tumorigenesis and associate with a poor prognosis of colorectal carcinoma patients. Sci Rep 4:7481. https://doi.org/10.1038/srep07481CrossRefPubMedPubMedCentral

16.

Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, Manos M, Gjini E, Kuchroo JR, Ishizuka JJ, Collier JL, Griffin GK, Maleri S, Comstock DE, Weiss SA, Brown FD, Panda A, Zimmer MD, Manguso RT, Hodi FS, Rodig SJ, Sharpe AH, Haining WN (2019) Subsets of exhausted CD8(+) T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 20(3):326–336. https://doi.org/10.1038/s41590-019-0312-6CrossRefPubMedPubMedCentral

17.

Song Q, Shi F, Adair M, Chang H, Guan X, Zhao Y, Li Y, Wu G, Wu J (2019) Cell counts, rather than proportion, of CD8/PD-1 Tumor-infiltrating lymphocytes in a tumor microenvironment associated with pathological characteristics of Chinese invasive ductal breast cancer. J Immunol Res 2019:8505021. https://doi.org/10.1155/2019/8505021CrossRefPubMedPubMedCentral

18.

Syed Khaja AS, Toor SM, El Salhat H, Ali BR, Elkord E (2017) Intratumoral FoxP3(+)Helios(+) regulatory T Cells upregulating immunosuppressive molecules are expanded in human colorectal cancer. Front Immunol 8:619. https://doi.org/10.3389/fimmu.2017.00619CrossRefPubMedPubMedCentral

19.

Aibar S, Abaigar M, Campos-Laborie FJ, Sanchez-Santos JM, Hernandez-Rivas JM, De Las RJ (2016) Identification of expression patterns in the progression of disease stages by integration of transcriptomic data. BMC Bioinf 17(Suppl 15):432. https://doi.org/10.1186/s12859-016-1290-4CrossRef

20.

Rahimi A, Gonen M (2018) Discriminating early- and late-stage cancers using multiple kernel learning on gene sets. Bioinformatics 34(13):i412–i421. https://doi.org/10.1093/bioinformatics/bty239CrossRefPubMedPubMedCentral

21.

Elashi AA, Sasidharan Nair V, Taha RZ, Shaath H, Elkord E (2019) DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients. Oncoimmunology 8(2):e1542918. https://doi.org/10.1080/2162402X.2018.1542918CrossRefPubMed

22.

Xu L, Li M, Wang M, Yan D, Feng G, An G (2014) The expression of microRNA-375 in plasma and tissue is matched in human colorectal cancer. BMC Cancer 14:714. https://doi.org/10.1186/1471-2407-14-714CrossRefPubMedPubMedCentral

23.

Jiang Y, Li Y, Zhu B (2015) T-cell exhaustion in the tumor microenvironment. Cell Death Dis 6:e1792. https://doi.org/10.1038/cddis.2015.162CrossRefPubMedPubMedCentral

24.

Kahan SM, Zajac AJ (2019) Immune exhaustion: past lessons and new insights from lymphocytic choriomeningitis virus. Viruses. https://doi.org/10.3390/v11020156CrossRefPubMedPubMedCentral

25.

Hong JJ, Amancha PK, Rogers K, Ansari AA, Villinger F (2013) Re-evaluation of PD-1 expression by T cells as a marker for immune exhaustion during SIV infection. PLoS ONE 8(3):e60186. https://doi.org/10.1371/journal.pone.0060186CrossRefPubMedPubMedCentral

26.

Shembrey C, Huntington ND, Hollande F (2019) Impact of tumor and immunological heterogeneity on the anti-cancer immune response. Cancers (Basel). https://doi.org/10.3390/cancers11091217CrossRefPubMedCentral

27.

Toor SM, Murshed K, Al-Dhaheri M, Khawar M, Abu Nada M, Elkord E (2019) Immune checkpoints in circulating and tumor-infiltrating cd4+ t cell subsets in colorectal cancer patients. Frontiers Immunol 10:2936CrossRef

28.

Yu DF, Jiang SJ, Pan ZP, Cheng WD, Zhang WJ, Yao XK, Li YC, Lun YZ (2016) Expression and clinical significance of Sirt1 in colorectal cancer. Oncol Lett 11(2):1167–1172. https://doi.org/10.3892/ol.2015.3982CrossRefPubMed

29.

Mitrovic B, Schaeffer DF, Riddell RH, Kirsch R (2012) Tumor budding in colorectal carcinoma: time to take notice. Mod Pathol 25(10):1315–1325. https://doi.org/10.1038/modpathol.2012.94CrossRefPubMed

30.

Blank A, Schenker C, Dawson H, Beldi G, Zlobec I, Lugli A (2019) Evaluation of tumor budding in primary colorectal cancer and corresponding liver metastases based on H&E and pancytokeratin staining. Front Med (Lausanne) 6:247. https://doi.org/10.3389/fmed.2019.00247CrossRef

31.

Sasidharan Nair V, Toor SM, Taha RZ, Shaath H, Elkord E (2018) DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer. Clin Epigenet 10(1):104. https://doi.org/10.1186/s13148-018-0539-3CrossRef

32.

Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, Elco CP, Lee N, Juneja VR, Zhan Q, Lian CG, Thomi R, Hoetzenecker W, Cozzio A, Dummer R, Mihm MC Jr, Flaherty KT, Frank MH, Murphy GF, Sharpe AH, Kupper TS, Schatton T (2015) Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162(6):1242–1256. https://doi.org/10.1016/j.cell.2015.08.052CrossRefPubMedPubMedCentral

33.

Grosso JF, Jure-Kunkel MN (2013) CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun 13:5PubMedPubMedCentral

34.

Rotte A (2019) Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 38(1):255. https://doi.org/10.1186/s13046-019-1259-zCrossRefPubMedPubMedCentral

35.

Kang CW, Dutta A, Chang LY, Mahalingam J, Lin YC, Chiang JM, Hsu CY, Huang CT, Su WT, Chu YY, Lin CY (2015) Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Sci Rep 5:15659. https://doi.org/10.1038/srep15659CrossRefPubMedPubMedCentral

36.

Zhou XM, Li WQ, Wu YH, Han L, Cao XG, Yang XM, Wang HF, Zhao WS, Zhai WJ, Qi YM, Gao YF (2018) Intrinsic expression of immune checkpoint molecule TIGIT could help tumor growth in vivo by suppressing the function of NK and CD8(+) T cells. Front Immunol 9:2821. https://doi.org/10.3389/fimmu.2018.02821CrossRefPubMedPubMedCentral

37.

Greenberg SA, Kong SW, Thompson E, Gulla SV (2019) Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models. Oncotarget 10(14):1399–1406. https://doi.org/10.18632/oncotarget.26659CrossRefPubMedPubMedCentral

38.

Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, Heuston EF, Kirby M, Anderson S, Cheng J, Khan O, Handon R, Reilley J, Fioravanti J, Hu J, Gossa S, Wherry EJ, Gattinoni L, McGavern DB, O'Shea JJ, Schwartzberg PL, Wu T (2019) Single-cell RNA-seq reveals TOX as a key regulator of CD8(+) T cell persistence in chronic infection. Nat Immunol 20(7):890–901. https://doi.org/10.1038/s41590-019-0403-4CrossRefPubMedPubMedCentral

39.

Zhu L, Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Palmisiano ND, Wang M, Jia B, Bayerl M, Schell TD, Hohl RJ, Zeng H, Zheng H (2017) Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia. J Hematol Oncol 10(1):124. https://doi.org/10.1186/s13045-017-0486-zCrossRefPubMedPubMedCentral

40.

Warren JL, MacIver NJ (2019) Regulation of adaptive immune cells by sirtuins. Front Endocrinol (Lausanne) 10:466. https://doi.org/10.3389/fendo.2019.00466CrossRef

41.

Li LT, Jiang G, Chen Q, Zheng JN (2015) Ki67 is a promising molecular target in the diagnosis of cancer (review). Mol Med Rep 11(3):1566–1572. https://doi.org/10.3892/mmr.2014.2914CrossRefPubMed

42.

Sciortino M, Camacho-Leal MdP, Orso F, Grassi E, Costamagna A, Provero P, Tam W, Turco E, Defilippi P, Taverna D, Cabodi S (2017) Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion. Sci Rep 7(1):1145. https://doi.org/10.1038/s41598-017-01332-zCrossRefPubMedPubMedCentral

43.

Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, Wherry EJ (2014) Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity 40(2):289–302. https://doi.org/10.1016/j.immuni.2014.01.005CrossRefPubMedPubMedCentral

44.

Xu B, Yuan L, Gao Q, Yuan P, Zhao P, Yuan H, Fan H, Li T, Qin P, Han L, Fang W, Suo Z (2015) Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer. Oncotarget 6(24):20592–20603. https://doi.org/10.18632/oncotarget.4112CrossRefPubMedPubMedCentral

45.

Zhou E, Huang Q, Wang J, Fang C, Yang L, Zhu M, Chen J, Chen L, Dong M (2015) Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer. Int J Clin Exp Pathol 8(7):8018–8027PubMedPubMedCentral

Title: Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer
Authors: Reem Saleh
Rowaida Z. Taha
Salman M. Toor
Varun Sasidharan Nair
Khaled Murshed
Mahwish Khawar
Mahmood Al-Dhaheri
Mahir Abdulla Petkar
Mohamed Abu Nada
Eyad Elkord
Publication date: 01-10-2020
Publisher: Springer Berlin Heidelberg
Keywords: Colorectal Cancer
Colorectal Cancer
Biomarkers
Published in: Cancer Immunology, Immunotherapy / Issue 10/2020
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-020-02593-w

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 10/2020

Successful treatment of steroid-refractory immune checkpoint inhibitor-related pneumonitis with triple combination therapy: a case report

The effects of tumor resection and adjuvant therapy on the peripheral blood immune cell profile in patients with colon carcinoma

A TLR4–TRIF-dependent signaling pathway is required for protective natural tumor-reactive IgM production by B1 cells

Expression of programmed death-ligand 1 (PD-L1) in human pituitary neuroendocrine tumor

PD-L1 expression correlates with tumor-infiltrating lymphocytes and better prognosis in patients with HPV-negative head and neck squamous cell carcinomas

Galectin-9 expression as a poor prognostic factor in patients with renal cell carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer