Annals of Surgical Oncology

, Volume 18, Issue 13, pp 3848–3857

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

  • Andrew J. Russ
  • Lucy Wentworth
  • Kyle Xu
  • Alexander Rakhmilevich
  • Christine M. Seroogy
  • Paul M. Sondel
  • M. Suresh
  • Clifford S. Cho
Translational Research and Biomarkers
  • 105 Downloads

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)

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Copyright information

© Society of Surgical Oncology 2011

Authors and Affiliations

  • Andrew J. Russ
    • 1
  • Lucy Wentworth
    • 1
    • 2
  • Kyle Xu
    • 1
  • Alexander Rakhmilevich
    • 3
  • Christine M. Seroogy
    • 4
  • Paul M. Sondel
    • 3
    • 4
  • M. Suresh
    • 5
  • Clifford S. Cho
    • 1
    • 2
  1. 1.Section of Surgical OncologyUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.William S. Middleton Memorial VA HospitalMadisonUSA
  3. 3.Department of Human OncologyUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  4. 4.Department of PediatricsUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  5. 5.Department of Pathobiological SciencesUniversity of Wisconsin School of Veterinary MedicineMadisonUSA

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