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. 2012 Sep 25;107(7):1107-15.
doi: 10.1038/bjc.2012.362. Epub 2012 Aug 21.

Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies

M J McCoy  1 , R A Lake, R G van der Most, I M Dick, A K Nowak
Affiliations

Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies

M J McCoy et al. Br J Cancer. .

Abstract

Background: There is increasing interest in combining chemotherapy with immunotherapy. However, the effects of chemotherapy on the human immune system are largely unknown.

Methods: Longitudinal changes in peripheral T-cell subsets in 40 patients with malignant mesothelioma (MM) or advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy were assessed by flow cytometry and evaluated for associations with clinical outcome.

Results: Proliferating T cells of all subsets were almost entirely depleted at day 8 following chemotherapy, but rapidly recovered above baseline levels. Regulatory T cells (Treg) were most profoundly depleted at this time point. A greater increase in CD8(+) T-cell proliferation following one treatment cycle was associated with improved overall survival in univariate (hazard ratio (HR)=0.40; P<0.05) and multivariate (HR=0.17; P<0.01) analyses. A greater increase in the ratio of CD8(+) T cell to Treg proliferation was also predictive of better prognosis.

Conclusion: Chemotherapy potentially provides a favourable environment for the development of anti-tumour immunity through transient Treg depletion and regeneration of the T-cell pool. Change in CD8(+) T-cell proliferation after one cycle of chemotherapy may represent a useful prognostic indicator in patients with MM and NSCLC.

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Figures

Figure 1
Figure 1
Lymphocyte counts during chemotherapy. (A) Total lymphocyte count. Broken line represents the lower limit of normal range. (B) Total lymphocyte count by disease group. (C) Proportion of CD4+ and CD8+ T cells. (D) CD8+ and CD4+ T-cell numbers. (E) Proportion of Foxp3+CD127lo Treg. (F) Treg numbers. Graphs show mean±s.e.m. *P<0.05, **P<0.01, ***P<0.001 relative to baseline. Time points were compared using a linear mixed model. Abbreviations: BL=baseline; C1D8=cycle 1 day 8; End C1=end of cycle 1; End C3=end of cycle 3.
Figure 2
Figure 2
The effect of chemotherapy on T-cell proliferation. (A) Ki67 expression by CD8+ and CD8− (CD4+) T cells from a representative patient. Plots are gated on CD3+ lymphocytes. (B, C, D) Proportions of proliferating (Ki67+) CD8+ T cells (B), CD4+ T cells (C) and Treg (D) in all patients during chemotherapy. (E) Ki67 expression by Treg vs CD8+ T cells and total CD4+ T cells in all patients at baseline. Graphs show median and IQR. Time points were compared using a linear mixed model (B, C, D) and T-cell subsets using the Wilcoxon signed rank test (E). *P<0.05, **P<0.01, ***P<0.001.
Figure 3
Figure 3
The effect of chemotherapy on activated effector T cells. (A) HLA-DR+CD38+ effector CD8+ T cells from a representative patient, values shown are percentage of total CD8+ T cells. (B) The proportion of effector CD8+ T cells in all patients during chemotherapy. Graph shows median and interquartile range. Time points were compared using a linear mixed model; ***P<0.001. (C) Bcl-2 expression in HLA-DR+CD38+ effector CD8+ T cells (solid line) vs HLA-DR−CD38− naive CD8+ T cells (broken line). Shaded area represents the corresponding isotype control.
Figure 4
Figure 4
Change in CD8+ T cell proliferation after one cycle of chemotherapy predicts survival. Kaplan–Meier analyses of overall survival in patients with a greater-than-median increase in proliferating CD8+ T cells (A) or in the ratio of proliferating CD8+ T cells to proliferating Treg (B) after one cycle of chemotherapy (solid line) vs patients with a below median increase/decrease (broken line). Groups were compared using the log rank test. Circles represent censored observations.
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