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

Our plain-English summary of Post-chemotherapy T-cell recovery is a marker of improved survival in patients with advanced thoracic malignancies, by M.J. McCoy, R.A. Lake, R.G. van der Most, et al (British Journal of Cancer, 2012).

The study

• Authors: M.J. McCoy, R.A. Lake, R.G. van der Most, I.M. Dick, A.K. Nowak
• Journal: British Journal of Cancer
• Published: 2012;107(7):1107-15
• Cited by: 60 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study followed patients with malignant mesothelioma (MM) or advanced non-small cell lung cancer (NSCLC) starting platinum-based chemotherapy. It tracked changes in their T cells, a type of immune cell, and whether those changes were linked to survival. Of 43 patients enrolled from 2007 to 2009 (27 with MM, 26 pleural and 1 peritoneal; 16 with NSCLC), 40 remained after three withdrew. Blood was tested before treatment and three times after. Dividing T cells almost vanished a week after the first dose. By the end of cycles 1 and 3, the share of T cells that were dividing was above starting levels, although total T-cell counts gradually fell. Patients whose share of dividing CD8+ T cells rose by the median (39.8%) or more after one cycle lived longer: hazard ratio 0.40 (95% CI 0.18 to 0.88) univariate and 0.17 (95% CI 0.05 to 0.56) multivariate, with median survival of 18.1 versus 8.1 months. No measure predicted time to progression or tumour response. The authors concluded this change could be a simple early prognostic test. They noted small numbers, a mixed group, patient loss, many hypotheses tested, and possible dexamethasone effects. Asbestos exposure was not studied.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Prospective longitudinal study of a patient cohort. Blood T-cell subsets were measured by flow cytometry before chemotherapy and at cycle 1 day 8, end of cycle 1 and end of cycle 3, and the changes were analysed for associations with clinical outcome.
• Who was studied: 43 patients enrolled 2007 to 2009 (authors based in Perth, Western Australia): 27 with malignant mesothelioma (26 pleural, 1 peritoneal) and 16 with non-small cell lung cancer. Mean age was 65 and 9 were female. Three withdrew after a baseline sample, leaving 40. One patient was excluded from analyses for a protocol violation (continuous dexamethasone use).
• Exposure: Platinum-based chemotherapy, not asbestos. Patients with MM received pemetrexed plus cisplatin (n = 19) or carboplatin (n = 6). Most patients with NSCLC received carboplatin with gemcitabine (n = 12); 3 received carboplatin plus paclitaxel. All regimens used 21-day cycles. The study did not examine asbestos exposure.
• Main results:
  • Median overall survival in all patients was 10.7 months and median time to progression was 6.3 months. Neither differed between patients with MM and NSCLC.
  • Total lymphocyte count fell significantly one week after the first dose (mean 1.50 x 10^9 per litre at baseline vs 1.30 at cycle 1 day 8, P less than 0.01). It kept declining more slowly (1.23 after cycle 1, 1.21 after cycle 3). CD8+ and CD4+ T-cell counts gradually decreased during treatment.
  • Proliferating (Ki67+) CD8+ T cells, CD4+ T cells and regulatory T cells (Tregs) were almost completely depleted one week after treatment. By the end of cycles 1 and 3, the proportions of proliferating cells were significantly above baseline.
  • The proportion of Tregs fell significantly at cycle 1 day 8 (mean 5.8% to 4.8% of total CD4+ T cells, P less than 0.01) and returned to baseline by the end of cycles 1 and 3. Treg numbers were reduced at cycle 1 day 8 but did not decrease further.
  • In all patients analysed, a greater-than-median percentage increase in proliferating CD8+ T cells from baseline to the end of cycle 1 was associated with better overall survival. Univariate: HR 0.40 (95% CI 0.18 to 0.88), P less than 0.05. Multivariate: HR 0.17 (95% CI 0.05 to 0.56), P less than 0.01.
  • Patients whose proliferating CD8+ T cells changed by 39.8% (the median) or more had a median survival of 18.1 months. Patients with a smaller increase or a decrease had a median survival of 8.1 months (P = 0.02).
  • A greater increase in the ratio of proliferating CD8+ T cells to proliferating Tregs after one cycle was also associated with better overall survival. Univariate: HR 0.36 (95% CI 0.16 to 0.78), P = 0.010. Multivariate: HR 0.29 (95% CI 0.12 to 0.73), P = 0.009.
  • Of the known prognostic factors, only ECOG performance status was a significant predictor (univariate HR 2.21, multivariate HR 2.43). The hazard ratio for gender (0.49) was not statistically significant.
  • No immunological or clinical variable predicted time to progression or best radiological response.
• The authors' conclusion: The authors concluded that chemotherapy-induced lymphodepletion may be beneficial through temporary removal of Treg-mediated suppression and/or regeneration of the T-cell pool. They also concluded that change in CD8+ T-cell proliferation after one cycle, although not predictive of short-term radiological response, could be a simple and early prognostic test for patients receiving standard chemotherapy.
• Limitations the authors state:
  • Relatively small numbers, a heterogeneous patient group, patient loss, and the number of immunological hypotheses tested.
  • Correction for multiple comparisons was not conducted, because analyses followed pre-determined hypotheses.
  • Histology and tumour stage could not be included in the survival model, because the two disease groups are not comparable on these variables.
  • Patient numbers did not allow regression analyses to be performed separately by diagnosis.
  • Dexamethasone given with the chemotherapy may have contributed to the observed effects on T-cell subsets.
  • The results should be validated in a larger and more uniform patient cohort.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Immunotherapy, Mesothelioma, Non-Small Cell Lung Cancer, Overall Survival, Hazard Ratio, Prognosis.

Related studies

• Peripheral CD8(+) T cell proliferation is prognostic for patients with advanced thoracic malignancies — M.J. McCoy, A.K. Nowak, et al. (2013)
• High-intensity statins are associated with improved clinical activity of PD-1 inhibitors in malignant pleural mesothelioma and advanced non-small cell lung cancer patients — L. Cantini, F. Pecci, et al. (2021)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers — A.M. Cook, A. McDonnell, et al. (2021)
• Serial immunomonitoring of cancer patients receiving combined antagonistic anti-CD40 and chemotherapy reveals consistent and cyclical modulation of T cell and dendritic cell parameters — A.M. McDonnell, A. Cook, et al. (2017)
• Simple nutritional intervention in patients with advanced cancers of the gastrointestinal tract, non-small cell lung cancers or mesothelioma and weight loss receiving chemotherapy: a randomised controlled trial — C. Baldwin, A. Spiro, et al. (2011)

Browse more research in British Journal of Cancer, or return to medical research.