Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study

Aditi Narsale, Rosa Moya, Jasmin Ma, Lindsey J Anderson, Daniel Wu, Jose M Garcia, Joanna D Davies, Aditi Narsale, Rosa Moya, Jasmin Ma, Lindsey J Anderson, Daniel Wu, Jose M Garcia, Joanna D Davies

Abstract

Background: Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4+ precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti-cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer.

Methods: The frequency of circulating CD4+ and CD8+ naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real-time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one-repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual-energy X-ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses.

Results: Our data show significant correlations between (i) higher frequencies of CD8+ naïve (P = 0.02) and effector memory (P = 0.003) T cells and lower frequencies of CD8+ central memory T cells (P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index (P = 0.04), (iii) lower frequency of CD8+ T cells that express CD95 with greater stair climb power (P = 0.003), (iv) higher frequency of T cells that co-express CD197 and CD45RA and greater one-repetition maximum knee extension strength (P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment (P = 0.004) in people with cancer.

Conclusions: We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow-up study with a larger cohort to test the validity of the findings.

Keywords: Cancer; Correlations; Flow cytometry; Muscle; T cells.

Conflict of interest statement

None declared.

© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Figures

Figure 1
Figure 1
Handgrip strength (HGS) and one‐repetition maximum chest press strength correlate with the frequency of circulating recent thymic emigrants (RTEs), central memory (CM), and effector memory (EM) in subjects with, but not without, cancer. Peripheral blood mononuclear cells were isolated from fresh whole blood and labelled for naïve and memory cell subsets as described in Materials and methods section and Table2. Panel A shows the correlation between the frequency of naïve CD8+ T cells that express CD31 but not Ki67 (CD8+ RTE, n = 7), CD8+ T cells that are CM (CD8+ CM, n = 9), and CD8+ memory cells that are EM (CD8+ EM, n = 9) and either HGS or chest press strength in the cancer group. Each symbol represents a patient. Spearman correlation (r) and statistical significance (P) are shown on each panel in red for the cancer group and in black for the non‐cancer group. (B) The frequency of each cell subset in people with cancer is compared with non‐cancer‐matched controls using the Student's t‐test. Data shown are mean ± SEM. There is no statistically significant difference between groups.
Figure 2
Figure 2
T cells and non‐T cells, identified by their co‐expression of CD197 and CD45RA, correlate with muscle strength and performance. The frequency of CD197+ CD3+ (A) and CD197+ CD3− (B) cells that express CD45RA. Correlations with handgrip strength (HGS, chest press strength, knee extension strength, and stair climb power (SCP) were calculated. Each symbol represents a participant. Spearman correlation (r) and statistical significance (P) are shown on each panel for the cancer group.
Figure 3
Figure 3
CD197 expression is significantly reduced in people with cancer. CD197 mRNA expression in whole blood from people with (n = 11) and without (n = 9) cancer was quantified using real‐time RT‐PCR (A). CD197 and CD45RA protein expression was determined on a single western blot (B and C). Panel B shows the combined data from all samples in both groups. Panel C shows all samples from each group on the same gel. Groups are compared using the Student's t‐test. Data shown are mean ± SEM. The P value is shown on panel A.
Figure 4
Figure 4
The frequency of CD95+ T cells and non‐T cells correlates with lower body muscle strength in people with cancer. Correlations between relative frequency of CD8+ CD95+ T cells and stair climb power (SCP) (A) and knee extension strength (B). Correlations between the relative frequency of CD3− peripheral blood mononuclear cell (PBMC) in people with cancer that express CD95 and either SCP (C) or knee extension strength (D). Spearman correlation (r) and statistical significance (P) are shown on panels A–D. Each symbol represents a single participant.
Figure 5
Figure 5
The level of CD95 gene expression in whole blood correlates with muscle strength. CD95 mRNA in whole blood (A) and CD95 and caspase 3 protein expression in peripheral blood mononuclear cell (B and C) was quantified using real‐time RT‐PCR and western blot from people with (n = 11) and without (n = 9) cancer. Panel B shows the combined data from all samples in both groups. Panel C shows all samples from each group on the same gel. Groups were compared using the Student's t‐test. Data shown are mean ± SEM. The P value is shown on panel A. Spearman correlations (r) in the group with cancer are shown between the levels of CD95 mRNA expression in whole blood, quantified by real‐time RT‐PCR, and either knee extension strength (D) or stair climb power (SCP) (E).
Figure 6
Figure 6
Treg cell frequency correlates with a low lean mass index (LMI) in people with cancer. Correlations between the relative frequency of Treg (A) with LMI in people with cancer. The LMI shown is the LMI in kg/m2 × 1000. Spearman correlation (r) and statistical significance (P) are shown. Panel B, Treg cell frequency, is compared between groups using the Student's t‐test. Data shown are mean ± SEM.
Figure 7
Figure 7
Interleukin (IL) 2‐expressing CD8+ T cells and body composition. Correlations between the relative frequency IL‐2 expressing CD8+ T cells and either lean mass index (LMI) (A) or body mass index (BMI) (B) in people with cancer (n = 8). The LMI shown is the LMI in kg/m2 × 1000. Spearman correlation (r) and statistical significance (P) are shown on panels A and B. Each symbol represents a single participant. Panel C, IL‐2+ CD8+ cell subset frequency, is compared between groups with (n = 8) and without (n = 8) cancer using the Student's t‐test. Data shown are mean ± SEM.
Figure 8
Figure 8
Immune correlations with the Karnofsky Performance Scale Index and ECOG‐PS. The level of CD4 expression in whole blood from people with (n = 11) and without (n = 9) cancer was determined by real‐time RT‐PCR. In the same subjects, performance was determined using both the Karnofsky index and the ECOG‐PS. Panels A and B compare the Karnofsky index (A) and ECOG‐PS (B) in people with and without cancer. Correlations between CD4 levels and either the Karnofsky index (C) or the ECOG‐PS (D) are shown for people with cancer. In panels A and B, groups are compared using the Student's t‐test. Data shown are mean ± SEM. The P value is shown on each panel. Spearman correlation (r) and statistical significance (P) are shown on panels C and D for the cancer group. Data are not significant for the non‐cancer group.

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