Immune Signaling in Carcinogenesis

  • Mahesh Yadav
  • Marcin Kowanetz
  • Hartmut KoeppenEmail author


Cancer immunotherapy strategies involve manipulating patients’ immune system to augment tumor immunity and represent a paradigm shift in the treatment cancer . Main immunotherapeutic strategies include regimes such as cytokines, vaccines, an oncolytic virus, adoptive cell therapy, and immune checkpoint blockade. The approach that has sparked the most interest involves inhibition or activation of specific immune checkpoints to regulate T cell function in order to boost patients’ own ability to fight cancer. Under normal physiological conditions, the immune checkpoints are crucial for maintaining self-tolerance to prevent autoimmunity and also to protect tissues from damage during infections. However, in cancer, the function of immune checkpoints is dysregulated in order to suppress the ongoing T cell-mediated antitumor immune responses. Numerous inhibitory (e.g., CTLA-4, PD-1, TIGIT, LAG3, IDO) as well as stimulatory (e.g., OX40, 4-1BB, CD27, STING) immune signaling pathways are being currently targeted for cancer immunotherapy. Two of them, CTLA-4 and PD-1, have been most actively studied in the clinic up till now, and numerous positive clinical trials led to approval of therapies targeting these two pathways across several tumor types. However, despite these significant advances, the majority of patients do not respond favorably to cancer immunotherapies. This may be due to additional mechanisms that can influence the enhancement of T cell function at play, in addition to multiple mechanisms used by tumors to evade the immune system. Hence, future effective immunotherapies will likely involve novel combinations of different immunotherapeutic approaches in addition to targeted therapies that are personalized for maximal benefit.


Immune signaling Immune checkpoints Co-stimulation Cytotoxic T cells Immunotherapy 


  1. 1.
    Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016;44(5):1069–78. Scholar
  2. 2.
    Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56–61. Scholar
  3. 3.
    Ise W, Kohyama M, Nutsch KM, Lee HM, Suri A, Unanue ER, et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol. 2010;11(2):129–35. Scholar
  4. 4.
    Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13(5):273–90. Scholar
  5. 5.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. Scholar
  6. 6.
    Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol. 1998;10(10):1563–72.CrossRefPubMedGoogle Scholar
  7. 7.
    Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol. 2017;8:561. Scholar
  8. 8.
    Manieri NA, Chiang EY, Grogan JL. TIGIT: a key inhibitor of the cancer immunity cycle. Trends Immunol. 2017;38(1):20–8. Scholar
  9. 9.
    Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923–37. Scholar
  10. 10.
    Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989–1004. Scholar
  11. 11.
    Holmgaard RB, Zamarin D, Li Y, Gasmi B, Munn DH, Allison JP, et al. Tumor-expressed IDO recruits and activates MDSCs in a treg-dependent manner. Cell Rep. 2015;13(2):412–24. Scholar
  12. 12.
    Ledford H. (2017). Next-generation cancer drugs boost immunotherapy responses. Early clinical trial data suggest that combining medicines improves treatment. Nat News.
  13. 13.
    Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol. 2015;5:34. Scholar
  14. 14.
    Bartkowiak T, Curran MA. 4-1BB agonists: multi-potent potentiators of tumor immunity. Front Oncol. 2015;5:117. Scholar
  15. 15.
    van de Ven K, Borst J. Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential. Immunotherapy. 2015;7(6):655–67. Scholar
  16. 16.
    Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41(5):830–42. Scholar
  17. 17.
    Gilboa E. The promise of cancer vaccines. Nat Rev Cancer. 2004;4(5):401–11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Mahesh Yadav
    • 1
  • Marcin Kowanetz
    • 1
  • Hartmut Koeppen
    • 2
    Email author
  1. 1.Department of Oncology Biomarker DevelopmentGenentechSouth San FranciscoUSA
  2. 2.Research PathologyGenentechSouth San FranciscoUSA

Personalised recommendations