Annals of Surgical Oncology

, Volume 18, Issue 13, pp 3848–3857

Suppression of T-Cell Expansion by Melanoma is Exerted on Resting Cells

Authors

  • Andrew J. Russ
    • Section of Surgical OncologyUniversity of Wisconsin School of Medicine and Public Health
  • Lucy Wentworth
    • Section of Surgical OncologyUniversity of Wisconsin School of Medicine and Public Health
    • William S. Middleton Memorial VA Hospital
  • Kyle Xu
    • Section of Surgical OncologyUniversity of Wisconsin School of Medicine and Public Health
  • Alexander Rakhmilevich
    • Department of Human OncologyUniversity of Wisconsin School of Medicine and Public Health
  • Christine M. Seroogy
    • Department of PediatricsUniversity of Wisconsin School of Medicine and Public Health
  • Paul M. Sondel
    • Department of Human OncologyUniversity of Wisconsin School of Medicine and Public Health
    • Department of PediatricsUniversity of Wisconsin School of Medicine and Public Health
  • M. Suresh
    • Department of Pathobiological SciencesUniversity of Wisconsin School of Veterinary Medicine
    • Section of Surgical OncologyUniversity of Wisconsin School of Medicine and Public Health
    • William S. Middleton Memorial VA Hospital
Translational Research and Biomarkers

DOI: 10.1245/s10434-011-1667-6

Cite this article as:
Russ, A.J., Wentworth, L., Xu, K. et al. Ann Surg Oncol (2011) 18: 3848. doi:10.1245/s10434-011-1667-6

Abstract

Background

Immunotherapeutic cancer protocols often rely on the ability to promote proliferative expansion of tumor-specific T-cell, but the influence of cancer on in vivo T-cell expansion remains largely undefined.

Methods

The ability of control and B16F10 melanoma-bearing C57BL/6 mice to expand lymphocytic choriomeningitis virus antigen-specific T-cell populations in response to acute viral infection was compared by using flow cytometric assays of splenocytes.

Results

The ability to expand virus-specific CD8+ and CD4+ T-cells was globally and markedly suppressed in tumor-bearing mice. Expanded cytotoxic T lymphocytes (CTLs) retained in vivo and in vitro functionality, suggesting that melanoma growth did not induce T-cell anergy. The magnitude of suppressed proliferative expansion was proportional to the extent of tumor burden. Melanoma-induced suppression of CTL expansion was correlated with upregulated apoptotic activity and hampered the induction of memory precursor effector cells. Adoptive transfer of resting LCMV antigen-specific T-cells before or after tumor establishment demonstrated that a critical period of in vivo exposure of resting T-cells to growing melanoma was responsible for the induction of suppressed expansion. This suppression was durable; surgical resection of melanoma after in vivo exposure to resting T-cells but before antigenic stimulation did not restore full expansion.

Conclusions

These data suggest that growing melanoma tumors exert a global, antigen-independent influence on resting T-cells that fundamentally reprograms their ability to undergo proliferative expansion in response to subsequent antigenic stimulation. This finding may have direct implications for T-cell-based immunotherapeutic strategies.

Supplementary material

10434_2011_1667_MOESM1_ESM.doc (62 kb)
Supplementary Fig. 1 Timing of T-cell expansion and contraction is not altered in the presence of cancer. Splenocytes were harvested on day 16, 18, or 20 (corresponding to post-LCMV infection days 6, 8, and 10, respectively) and were analyzed by flow cytometry. Comparison of CTL populations specific for NP396 (a) and GP33 (b) identified a similar pattern of expansion and contraction between tumor-bearing mice (“tumor”) and non-tumor–bearing mice (“control”). Analysis of cellular proliferation as measured by Ki-67 high expression among NP396-specific CTLs (c) and GP33-specific CTLs (d) at the three time points showed no significant differences between tumor-bearing mice (“tumor”) and non-tumor–bearing mice (“control”). Analysis of cellular apoptosis as measured by Annexin Vhigh expression among NP396-specific CTLs (e) and GP33-specific CTLs (f) at the three time points showed more apoptotic activity on postinfection day 8 in tumor-bearing mice (“tumor”) compared with non-tumor–bearing mice (“control”). (g) Smaller populations of MPECs as measured by CD127 high/KLRGlow expression among NP396-specific and GP33-specific CTLs were observed in tumor-bearing mice (“tumor”) compared with non-tumor–bearing mice (“control”) on day 20 (DOC 61 kb)

Copyright information

© Society of Surgical Oncology 2011