Functional differences between low- and high-affinity CD8(+) T cells in the tumor environment
Rinke Bos, Kristi L Marquardt, Jocelyn Cheung, Linda A Sherman, Rinke Bos, Kristi L Marquardt, Jocelyn Cheung, Linda A Sherman
Abstract
Weak T-cell antigen receptor (TCR)-ligand interactions are sufficient to activate naïve CD8(+) T cells, but generally do not result in tumor eradication. How differences in TCR affinity affect the regulation of T-cell function in an immunosuppressive tumor environment has not been investigated. We have examined the functional differences of high- vs. low-affinity CD8(+) T cells and we observed that infiltration, accumulation, survival and cytotoxicity within the tumor are severely impacted by the strength of TCR-ligand interactions. In addition, high-affinity CD8(+) T cells were found to exhibit lower expression of inhibitory molecules including PD-1, LAG-3 and NKG2A, thus being less susceptible to suppressive mechanisms. Interferon γ and autocrine interleukin-2 were both found to influence the level of expression of these molecules. Interestingly, although high-affinity CD8(+) T cells were superior to low-affinity CD8(+) T cells in their ability to effect tumor eradication, they could be further improved by the presence of tumor specific CD4(+) T cells. These findings illustrate the importance of both TCR affinity and tumor-specific CD4 help in tumor immunotherapy.
Figures
References
- Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571–606. doi: 10.1146/annurev.immunol.23.021704.115601.
- Sprent J, Kishimoto H. The thymus and negative selection. Immunol Rev. 2002;185:126–35. doi: 10.1034/j.1600-065X.2002.18512.x.
- Miller JF, Kurts C, Allison J, Kosaka H, Carbone F, Heath WR. Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens. Immunol Rev. 1998;165:267–77. doi: 10.1111/j.1600-065X.1998.tb01244.x.
- Bouneaud C, Kourilsky P, Bousso P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity. 2000;13:829–40. doi: 10.1016/S1074-7613(00)00080-7.
- Nugent CT, Morgan DJ, Biggs JA, Ko A, Pilip IM, Pamer EG, et al. Characterization of CD8+ T lymphocytes that persist after peripheral tolerance to a self antigen expressed in the pancreas. J Immunol. 2000;164:191–200.
- Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003;21:807–39. doi: 10.1146/annurev.immunol.21.120601.141135.
- Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 2005;437:141–6. doi: 10.1038/nature03954.
- Klebanoff CA, Acquavella N, Yu Z, Restifo NP. Therapeutic cancer vaccines: are we there yet? Immunol Rev. 2011;239:27–44. doi: 10.1111/j.1600-065X.2010.00979.x.
- Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10:909–15. doi: 10.1038/nm1100.
- Bos R, Sherman LA. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res. 2010;70:8368–77. doi: 10.1158/0008-5472.CAN-10-1322.
- Wong SB, Bos R, Sherman LA. Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J Immunol. 2008;180:3122–31.
- Merhavi-Shoham E, Haga-Friedman A, Cohen CJ. Genetically modulating T-cell function to target cancer. Semin Cancer Biol. 2012;22:14–22. doi: 10.1016/j.semcancer.2011.12.006.
- Jorritsma A, Gomez-Eerland R, Dokter M, van de Kasteele W, Zoet YM, Doxiadis II, et al. Selecting highly affine and well-expressed TCRs for gene therapy of melanoma. Blood. 2007;110:3564–72. doi: 10.1182/blood-2007-02-075010.
- Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114:535–46. doi: 10.1182/blood-2009-03-211714.
- Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126–9. doi: 10.1126/science.1129003.
- Lyman MA, Nugent CT, Marquardt KL, Biggs JA, Pamer EG, Sherman LA. The fate of low affinity tumor-specific CD8+ T cells in tumor-bearing mice. J Immunol. 2005;174:2563–72.
- Dutoit V, Rubio-Godoy V, Dietrich PY, Quiqueres AL, Schnuriger V, Rimoldi D, et al. Heterogeneous T-cell response to MAGE-A10(254-262): high avidity-specific cytolytic T lymphocytes show superior antitumor activity. Cancer Res. 2001;61:5850–6.
- Alexander-Miller MA, Leggatt GR, Berzofsky JA. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci U S A. 1996;93:4102–7. doi: 10.1073/pnas.93.9.4102.
- Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678–89. doi: 10.1038/nri2156.
- Marelli-Berg FM, Cannella L, Dazzi F, Mirenda V. The highway code of T cell trafficking. J Pathol. 2008;214:179–89. doi: 10.1002/path.2269.
- Zehn D, Lee SY, Bevan MJ. Complete but curtailed T-cell response to very low-affinity antigen. Nature. 2009;458:211–4. doi: 10.1038/nature07657.
- Zeh HJ, 3rd, Perry-Lalley D, Dudley ME, Rosenberg SA, Yang JC. High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. J Immunol. 1999;162:989–94.
- Bullock TN, Mullins DW, Colella TA, Engelhard VH. Manipulation of avidity to improve effectiveness of adoptively transferred CD8(+) T cells for melanoma immunotherapy in human MHC class I-transgenic mice. J Immunol. 2001;167:5824–31.
- Savinov AY, Wong FS, Stonebraker AC, Chervonsky AV. Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells. J Exp Med. 2003;197:643–56. doi: 10.1084/jem.20021378.
- Savinov AY, Wong FS, Chervonsky AV. IFN-gamma affects homing of diabetogenic T cells. J Immunol. 2001;167:6637–43.
- Refaeli Y, Van Parijs L, Alexander SI, Abbas AK. Interferon gamma is required for activation-induced death of T lymphocytes. J Exp Med. 2002;196:999–1005. doi: 10.1084/jem.20020666.
- Badovinac VP, Tvinnereim AR, Harty JT. Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma. Science. 2000;290:1354–8. doi: 10.1126/science.290.5495.1354.
- Dalton DK, Haynes L, Chu CQ, Swain SL, Wittmer S. Interferon gamma eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J Exp Med. 2000;192:117–22. doi: 10.1084/jem.192.1.117.
- D’Souza WN, Lefrançois L. IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J Immunol. 2003;171:5727–35.
- Feau S, Arens R, Togher S, Schoenberger SP. Autocrine IL-2 is required for secondary population expansion of CD8(+) memory T cells. Nat Immunol. 2011;12:908–13. doi: 10.1038/ni.2079.
- Verdeil G, Marquardt K, Surh CD, Sherman LA. Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy. Proc Natl Acad Sci U S A. 2008;105:16683–8. doi: 10.1073/pnas.0805054105.
- Verdeil G, Puthier D, Nguyen C, Schmitt-Verhulst AM, Auphan-Anezin N. STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors. J Immunol. 2006;176:4834–42.
- Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107:7875–80. doi: 10.1073/pnas.1003345107.
- Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117:3383–92. doi: 10.1172/JCI31184.
- Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917–27. doi: 10.1158/0008-5472.CAN-11-1620.
- Sheu BC, Chiou SH, Lin HH, Chow SN, Huang SC, Ho HN, et al. Up-regulation of inhibitory natural killer receptors CD94/NKG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8+ T lymphocytes in human cervical carcinoma. Cancer Res. 2005;65:2921–9. doi: 10.1158/0008-5472.CAN-04-2108.
- Kessels HW, Schepers K, van den Boom MD, Topham DJ, Schumacher TN. Generation of T cell help through a MHC class I-restricted TCR. J Immunol. 2006;177:976–82.
- Morris EC, Tsallios A, Bendle GM, Xue SA, Stauss HJ. A critical role of T cell antigen receptor-transduced MHC class I-restricted helper T cells in tumor protection. Proc Natl Acad Sci U S A. 2005;102:7934–9. doi: 10.1073/pnas.0500357102.
- Kuball J, Schmitz FW, Voss RH, Ferreira EA, Engel R, Guillaume P, et al. Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity. 2005;22:117–29. doi: 10.1016/j.immuni.2004.12.005.
- Lyman MA, Aung S, Biggs JA, Sherman LA. A spontaneously arising pancreatic tumor does not promote the differentiation of naive CD8+ T lymphocytes into effector CTL. J Immunol. 2004;172:6558–67.
- Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000;132:365–86.
Source: PubMed