Skip to main content
SpringerLink
Log in

Cytotoxic CD8+ Lymphocytes in the Tumor Microenvironment

  • Chapter
  • First Online:
Tumor Microenvironment

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1224))

Abstract

In the tumor microenvironment, CD8+ T cells play a major role in tumor immunity. CD8+ T cells differentiate to cytotoxic T cells, traffic into the tumor microenvironment, and exhibit cytotoxicity against tumor cells. These processes have both positive and negative effects. Enhancements in the cytotoxic activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment are crucial for the development of cancer immunotherapy. To achieve this, several immunotherapies, including cancer vaccines, T cells engineered to express chimeric antigen receptors (CAR T cells), and bispecific T-cell engagers (BiTEs), have been developed. In contrast to cancer vaccines, CAR T cells, and BiTEs, immune checkpoint inhibitors enhance the activity of cytotoxic T cells by inhibiting the negative regulators of T cells.

The total number, type, and activity of tumor antigen-specific cytotoxic T cells in the tumor microenvironment need to be clarified, particularly for the development of companion diagnostics to identify patients for whom these therapies are effective. Therefore, technologies including TCR repertoire, single-cell, and T-cell cytotoxicity analyses using BiTEs have been developed.

Based on these and future innovations, the generation of effective cancer immunotherapies is anticipated.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461. https://doi.org/10.1016/j.ccell.2015.03.001. S1535-6108(15)00089-6 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kalia V et al (2010) Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32:91–103. https://doi.org/10.1016/j.immuni.2009.11.010. S1074-7613(10)00008-7 [pii]

    Article  CAS  PubMed  Google Scholar 

  3. Pipkin ME et al (2010) Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32:79–90. https://doi.org/10.1016/j.immuni.2009.11.012. S1074-7613(10)00010-5 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gebhardt T et al (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10:524–530. https://doi.org/10.1038/ni.1718. ni.1718 [pii]

    Article  CAS  PubMed  Google Scholar 

  5. Masopust D et al (2010) Dynamic T cell migration program provides resident memory within intestinal epithelium. J Exp Med 207:553–564. https://doi.org/10.1084/jem.20090858. jem.20090858 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cepek KL et al (1994) Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372:190–193. https://doi.org/10.1038/372190a0

    Article  CAS  PubMed  Google Scholar 

  7. Ganesan AP et al (2017) Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol 18:940–950. https://doi.org/10.1038/ni.3775. ni.3775 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schwartz JC, Zhang X, Fedorov AA, Nathenson SG, Almo SC (2001) Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 410:604–608. https://doi.org/10.1038/35069112. 35069112 [pii]

    Article  CAS  PubMed  Google Scholar 

  9. Stamper CC et al (2001) Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 410:608–611. https://doi.org/10.1038/35069118. 35069118 [pii]

    Article  CAS  PubMed  Google Scholar 

  10. Collins AV et al (2002) The interaction properties of costimulatory molecules revisited. Immunity 17:201–210. S1074-7613(02)00362-X [pii]

    Article  CAS  PubMed  Google Scholar 

  11. Hodi FS et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723. https://doi.org/10.1056/NEJMoa1003466. NEJMoa1003466 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Golstein P, Griffiths GM (2018) An early history of T cell-mediated cytotoxicity. Nat Rev Immunol 18:527–535. https://doi.org/10.1038/s41577-018-0009-3

    Article  CAS  PubMed  Google Scholar 

  13. Xu Y et al (2016) Glycolysis determines dichotomous regulation of T cell subsets in hypoxia. J Clin Invest 126:2678–2688. https://doi.org/10.1172/JCI85834. 85834 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y et al (2017) Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32:377–391.e379. https://doi.org/10.1016/j.ccell.2017.08.004. S1535-6108(17)30347-1 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zajac AJ et al (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188:2205–2213. https://doi.org/10.1084/jem.188.12.2205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hui E et al (2017) T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:1428–1433. https://doi.org/10.1126/science.aaf1292. science.aaf1292 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kamphorst AO et al (2017) Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423–1427. https://doi.org/10.1126/science.aaf0683. science.aaf0683 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44:989–1004. https://doi.org/10.1016/j.immuni.2016.05.001. S1074-7613(16)30155-8 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. van der Bruggen P et al (1991) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254:1643–1647. https://doi.org/10.1126/science.1840703

    Article  PubMed  Google Scholar 

  20. Finney HM, Lawson AD, Bebbington CR, Weir AN (1998) Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 161:2791–2797

    CAS  PubMed  Google Scholar 

  21. Hombach A et al (2001) Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. J Immunol 167:6123–6131. https://doi.org/10.4049/jimmunol.167.11.6123

    Article  CAS  PubMed  Google Scholar 

  22. Thompson CB et al (1989) CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines. Proc Natl Acad Sci U S A 86:1333–1337. https://doi.org/10.1073/pnas.86.4.1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733. https://doi.org/10.1056/NEJMoa1103849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brentjens RJ et al (2011) Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817–4828. https://doi.org/10.1182/blood-2011-04-348540. blood-2011-04-348540 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vignali D, Kallikourdis M (2017) Improving homing in T cell therapy. Cytokine Growth Factor Rev 36:107–116. https://doi.org/10.1016/j.cytogfr.2017.06.009. S1359-6101(17)30107-7 [pii]

    Article  CAS  PubMed  Google Scholar 

  26. Craddock JA et al (2010) Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother 33:780–788. https://doi.org/10.1097/CJI.0b013e3181ee6675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kloss CC et al (2018) Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther 26:1855–1866. https://doi.org/10.1016/j.ymthe.2018.05.003. S1525-0016(18)30206-5 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sukumaran S et al (2018) Enhancing the potency and specificity of engineered T cells for cancer treatment. Cancer Discov 8:972–987. https://doi.org/10.1158/2159-8290.CD-17-1298. 2159-8290.CD-17-1298 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hu J et al (2018) T-cell homing therapy for reducing regulatory T cells and preserving effector T-cell function in large solid tumors. Clin Cancer Res 24:2920–2934. https://doi.org/10.1158/1078-0432.CCR-17-1365. 1078-0432.CCR-17-1365 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Long AH et al (2016) Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol Res 4:869–880. https://doi.org/10.1158/2326-6066.CIR-15-0230. 2326-6066.CIR-15-0230 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. John LB et al (2013) Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res 19:5636–5646. https://doi.org/10.1158/1078-0432.CCR-13-0458. 1078-0432.CCR-13-0458 [pii]

    Article  CAS  PubMed  Google Scholar 

  32. Ninomiya S et al (2015) Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125:3905–3916. https://doi.org/10.1182/blood-2015-01-621474. blood-2015-01-621474 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Schreiner J et al (2016) Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor. Oncoimmunology 5:e1062969. https://doi.org/10.1080/2162402X.2015.1062969. 1062969 [pii]

    Article  CAS  PubMed  Google Scholar 

  34. Kantarjian H et al (2017) Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med 376:836–847. https://doi.org/10.1056/NEJMoa1609783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Frankel SR, Baeuerle PA (2013) Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol 17:385–392. https://doi.org/10.1016/j.cbpa.2013.03.029. S1367-5931(13)00054-9 [pii]

    Article  CAS  PubMed  Google Scholar 

  36. Iwahori K et al (2015) Engager T cells: a new class of antigen-specific T cells that redirect bystander T cells. Mol Ther 23:171–178. https://doi.org/10.1038/mt.2014.156.. S1525-0016(16)30022-3 [pii]

    Article  CAS  PubMed  Google Scholar 

  37. Bonifant CL et al (2016) CD123-engager T cells as a novel immunotherapeutic for acute myeloid leukemia. Mol Ther 24:1615–1626. https://doi.org/10.1038/mt.2016.116. S1525-0016(16)45337-2 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Velasquez MP et al (2016) T cells expressing CD19-specific engager molecules for the immunotherapy of CD19-positive malignancies. Sci Rep 6:27130. https://doi.org/10.1038/srep27130. srep27130 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Brahmer JR et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. https://doi.org/10.1056/NEJMoa1200694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Martinez P, Peters S, Stammers T, Soria JC (2019) Immunotherapy for the first-line treatment of patients with metastatic non-small cell lung cancer. Clin Cancer Res 25:2691–2698. https://doi.org/10.1158/1078-0432.CCR-18-3904. 1078-0432.CCR-18-3904 [pii]

    Article  PubMed  Google Scholar 

  42. Hu-Lieskovan S et al (2019) Tumor characteristics associated with benefit from pembrolizumab in advanced non-small cell lung cancer. Clin Cancer Res 25:5061–5068. https://doi.org/10.1158/1078-0432.CCR-18-4275. 1078-0432.CCR-18-4275 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  43. Riaz N et al (2017) Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171:934–949.e916. https://doi.org/10.1016/j.cell.2017.09.028. S0092-8674(17)31122-4 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Riaz N et al (2016) The role of neoantigens in response to immune checkpoint blockade. Int Immunol 28:411–419. https://doi.org/10.1093/intimm/dxw019. dxw019 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348:69–74. https://doi.org/10.1126/science.aaa4971. 348/6230/69 [pii]

    Article  CAS  PubMed  Google Scholar 

  46. Ott PA et al (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217–221. https://doi.org/10.1038/nature22991. nature22991 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Matsuda T et al (2018) Induction of neoantigen-specific cytotoxic t cells and construction of T-cell receptor-engineered T cells for ovarian cancer. Clin Cancer Res 24:5357–5367. https://doi.org/10.1158/1078-0432.CCR-18-0142. 1078-0432.CCR-18-0142 [pii]

    Article  PubMed  Google Scholar 

  48. Lawrence MS et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218. https://doi.org/10.1038/nature12213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pleasance ED et al (2010) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463:191–196. https://doi.org/10.1038/nature08658. nature08658 [pii]

    Article  CAS  PubMed  Google Scholar 

  50. Pleasance ED et al (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463:184–190. https://doi.org/10.1038/nature08629. nature08629 [pii]

    Article  CAS  PubMed  Google Scholar 

  51. Le Floc’h A et al (2007) Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J Exp Med 204:559–570. https://doi.org/10.1084/jem.20061524. jem.20061524 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zheng C et al (2017) Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell 169:1342–1356.e1316. https://doi.org/10.1016/j.cell.2017.05.035. S0092-8674(17)30596-2 [pii]

    Article  CAS  PubMed  Google Scholar 

  53. Egelston CA et al (2018) Human breast tumor-infiltrating CD8(+) T cells retain polyfunctionality despite PD-1 expression. Nat Commun 9:4297. https://doi.org/10.1038/s41467-018-06653-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Haas C et al (2009) Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology 214:441–453. https://doi.org/10.1016/j.imbio.2008.11.014. S0171-2985(08)00153-8 [pii]

    Article  CAS  PubMed  Google Scholar 

  55. Loffler A et al (2000) A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 95:2098–2103

    Article  CAS  PubMed  Google Scholar 

  56. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA (2006) Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol 43:763–771. https://doi.org/10.1016/j.molimm.2005.03.007. S0161-5890(05)00067-2 [pii]

    Article  CAS  PubMed  Google Scholar 

  57. Iwahori K et al (2019) Peripheral T cell cytotoxicity predicts T cell function in the tumor microenvironment. Sci Rep 9:2636. https://doi.org/10.1038/s41598-019-39345-5. 10.1038/s41598-019-39345-5 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. O’Brien SM et al (2019) Function of human tumor-infiltrating lymphocytes in early-stage non-small cell lung cancer. Cancer Immunol Res 7:896–909. https://doi.org/10.1158/2326-6066.CIR-18-0713. 2326-6066.CIR-18-0713 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

  59. Simoni Y et al (2018) Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557:575–579. https://doi.org/10.1038/s41586-018-0130-2.10.1038/s41586-018-0130-2 [pii]

    Article  CAS  PubMed  Google Scholar 

  60. Scheper W et al (2019) Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med 25:89–94. https://doi.org/10.1038/s41591-018-0266-5. 10.1038/s41591-018-0266-5 [pii]

    Article  CAS  PubMed  Google Scholar 

  61. Rosato PC et al (2019) Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat Commun 10:567. https://doi.org/10.1038/s41467-019-08534-1. 10.1038/s41467-019-08534-1 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lee PP et al (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5:677–685. https://doi.org/10.1038/9525

    Article  CAS  PubMed  Google Scholar 

  63. Gros A et al (2016) Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med 22:433–438. https://doi.org/10.1038/nm.4051. nm.4051 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Huang AC et al (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60–65. https://doi.org/10.1038/nature22079. nature22079 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dijkstra KK et al (2018) Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174:1586–1598.e1512. https://doi.org/10.1016/j.cell.2018.07.009. S0092-8674(18)30903-6 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pittet MJ, Garris CS, Arlauckas SP, Weissleder R (2018) Recording the wild lives of immune cells. Sci Immunol 3:eaaq0491. https://doi.org/10.1126/sciimmunol.aaq0491. 3/27/eaaq0491 [pii]

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author was supported by JSPS KAKENHI Grant Numbers 15K09218 and 18K08143.

Competing interests: The authors declare no competing interests.

Author information

Authors and Affiliations

  1. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan

    Kota Iwahori

  2. Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan

    Kota Iwahori

Authors
  1. Kota Iwahori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kota Iwahori .

Editor information

Editors and Affiliations

  1. Columbia University Medical Center, Department of Radiology, New York, NY, USA, Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil

    Alexander Birbrair

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Iwahori, K. (2020). Cytotoxic CD8+ Lymphocytes in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1224. Springer, Cham. https://doi.org/10.1007/978-3-030-35723-8_4

Download citation

Publish with us

Policies and ethics

Search

Navigation