Some CAR T therapies are approved and some are being investigated in clinical trials.

The Immune System Response to Target Cells


 

Immune system overview


Key players in immune surveillance


T cell subsets: A promising focus for adoptive cancer immunotherapy

A fundamental principle of cancer immunology is that cancer cells express antigens that the immune system can recognize to target for cell elimination.9

While there are a number of key players in this continual process of tumor immunosurveillance, T cells play an important role. T cells normally function to eliminate the body’s own cells that are infected or have become cancerous.10

T cell subsets are defined by the cell-surface markers and transcription factors they express and the cytokines they secrete, and are grouped by function.11 Subsets that have been used in approved or investigational CAR T cell therapies include12-14:

  • CD4+ (helper) T cells
  • CD8+ (cytotoxic) T cells
  • Regulatory T (Treg) cells
  • Gamma-delta (γδ) T cells
  • Natural killer T (NKT) cells

T cell differentiation begins in the thymus, where the majority of immature cells express an alpha-beta (αβ) T cell receptor (TCR) and both CD4 and CD8 co-receptors.15 The αβ TCR is responsible for recognizing major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells.15

Co-receptor binding with MHC determines an immature T cell’s differentiation into 2 main lineages15:

  • CD4+ T cells result when the CD4 co-receptor binds to MHC class II, ceasing CD8 expression
  • CD8+ T cells result when the CD8 co-receptor binds to MHC class I, ceasing CD4 expression

Naïve CD4+ and CD8+ T cells may undergo further differentiation into various memory and effector subsets upon antigen recognition in peripheral tissues.16,17

CD4+ T cells

Known as “helper” T cells because they help initiate and regulate immune responses. Each differentiated CD4+ subset releases specific cytokines that can support other immune cells and promote or suppress immune reactions.16,17 CD4+ T cells help activate B cells to secrete antibodies and macrophages to attack ingested microbes. CD4+ T cells help activate CD8+ T cells to kill target cells.18 In preclinical studies, CD4+ T cells were also shown to support CD8+ T cell memory functions.16,19,20

CD8+ cells

Known as “cytotoxic” T cells because they are specialized to recognize and directly attack target cells.10 As naïve CD8+ T cells differentiate from memory to effector subtypes, they trade off persistence and proliferative potential for shorter-lived cytotoxic potential.16

Regulatory T (Treg) cells

A subset of either immature T cells or CD4+ T cells, Treg cells are responsible for inhibiting immune responses.11,15 In preclinical studies, Treg cells and their ratio to effector T cells were shown to impact the effectiveness of anti-cancer immunotherapy.16 Conversely, the immunosuppressive properties of Treg cells are being investigated for use in transplant rejection and various autoimmune disorders.21

Gamma-delta (γδ) T cells

A minority of immature T cells express a gamma-delta TCR, and possess both innate and adaptive immune cell qualities with broad and potent anti-tumor activity, and both pro- and anti-inflammatory functions.11,22 These unconventional T cells do not require antigen presentation by MHC molecules and do not recognize the same antigens as αβ T cells.22

Natural killer T (NKT) cells

An uncommon T cell subset, NKT cells combine innate and adaptive immunity characteristics of natural killer cells and T cells, displaying pronounced, intrinsic anti-tumor activity.11,15,16,23


 

T cell activation

Effective T cell activation requires 2 concurrent signals: an activation signal and a co-stimulatory signal.


 

Tumor strategies to evade T cell immune response


Tumor evasion strategies can contribute to relapse and treatment resistance

In many cancer types, target cells are genetically diverse at diagnosis. Initial treatment with chemotherapy suppresses or kills the most aggressively multiplying cells but often leaves behind target cells with genetic mutations that allow them to continue multiplying despite ongoing therapy.25 While there have been significant advances in cancer treatment over the past 20 years, there is still a need for additional treatment approaches.


References: 1. Betts JG, Desaix P, Johnson E, et al. Anatomy and Physiology. OpenStax. 2017:1-1420. 2. Dranoff G. Nat Rev Cancer. 2004;4(1):11-22. 3. Chaplin D. J Allergy Clin Immunol. 2010;125(2 suppl 2):S3–S23. doi:10.1016/j.jaci.2009.12.980. 4. LeBien TW, Tedder TF. Blood. 2008;112:1570-1580. 5. Nature. Accessed November 21, 2018. 6. Janeway CA Jr, Travers P, Walport M, Shlomchik MJl. Immunobiology. 5th ed. 2001;258. 7. Nature. Accessed November 21, 2018. 8. Showalter A, Limaye A, Oyer JL, et al. Cytokine. 2017;97:123-132. 9. Finn OJ. Ann Oncol. 2012;23:viii6-viii9. 10. Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 9th ed. Philadelphia, PA: Saunders Elsevier; 2018. 11. Dong C, Martinez GJ. Nat Rev Immunol. 2010. Poster. 12. News release. Silver Spring, MD: Food and Drug Administration; October 18, 2017. Accessed January 11, 2019. 13. ClinicalTrials.gov. NCT03294954. Accessed September 29, 2018. 14. News release. Osaka, Japan: TC BioPharm; February 7, 2018. Accessed September 29, 2018. 15. ThermoFisher. Accessed September 29, 2018. 16. Golubovskaya V, Wu L. Cancers. 2016;8:36. doi:10.3390/cancers8030036. 17. Luckheeram RV, Zhou R, Verma AD, et al. Clin Dev Immunol. 2012;2012:925135. 18. Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th ed. 2002;1589. 19. Shedlock DJ, Shen H. Science. 2003;300:337-339. 20. Laidlaw BJ, Craft J, Kaech SM. Nat Rev Immunol. 2016;16:102-111. doi:10.1038/nri.2015.10. 21. News release. Richmond, CA: Sangamo Therapeutics; October 1, 2018. Accessed February 12, 2019. 22. Wu YL, Ding YP, Tanaka Y, et al. Int J Biol Sci. 2014;10:119-135. 23. Simon B, Wiesinger M, März J, et al. Int J Mol Sci. 2018;19:2365. 24. Maus MV, Levine BL. Oncologist. 2016;21:608-617. 25. Hunger SP, Mullighan CG. N Engl J Med. 2015;373:1541-1552.