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. 2022 Mar 4;14(5):1327.
doi: 10.3390/cancers14051327.

Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy

Mitchell S von Itzstein  1   2 , Amrit S Gonugunta  3 , Thomas Sheffield  4 , Jade Homsi  1   2 , Jonathan E Dowell  1   2 , Andrew Y Koh  5 , Prithvi Raj  6 , Farjana Fattah  2 , Yiqing Wang  4 , Vijay S Basava  2 , Shaheen Khan  6 , Jason Y Park  7 , Vinita Popat  3 , Jessica M Saltarski  2 , Yvonne Gloria-McCutchen  2 , David Hsiehchen  1   2 , Jared Ostmeyer  4 , Yang Xie  2   4 , Quan-Zhen Li  6 , Edward K Wakeland  6 , David E Gerber  1   2   4
Affiliations

Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy

Mitchell S von Itzstein et al. Cancers (Basel). .

Abstract

Antibiotic administration is associated with worse clinical outcomes and changes to the gut microbiome in cancer patients receiving immune checkpoint inhibitors (ICI). However, the effects of antibiotics on systemic immune function are unknown. We, therefore, evaluated antibiotic exposure, therapeutic responses, and multiplex panels of 40 serum cytokines and 124 antibodies at baseline and six weeks after ICI initiation, with p < 0.05 and false discovery rate (FDR) < 0.2 considered significant. A total of 251 patients were included, of whom the 135 (54%) who received antibiotics had lower response rates and shorter survival. Patients who received antibiotics prior to ICI initiation had modestly but significantly lower baseline levels of nucleolin, MDA5, c-reactive protein, and liver cytosol antigen type 1 (LC1) antibodies, as well as higher levels of heparin sulfate and Matrigel antibodies. After ICI initiation, antibiotic-treated patients had significantly lower levels of MDA5, CENP.B, and nucleolin antibodies. Although there were no clear differences in cytokines in the overall cohort, in the lung cancer subset (53% of the study population), we observed differences in IFN-γ, IL-8, and macrophage inflammatory proteins. In ICI-treated patients, antibiotic exposure is associated with changes in certain antibodies and cytokines. Understanding the relationship between these factors may improve the clinical management of patients receiving ICI.

Keywords: antibiotics; antibodies; biomarkers; cancer; cytokines; efficacy; immune checkpoint inhibitors; immunotherapy.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Best radiographic response according to antibiotic exposure: (a) any antibiotic exposure versus no antibiotic exposure; (b) antibiotic exposure pre-ICI initiation; (c) antibiotic exposure post-ICI initiation.
Figure 2
Figure 2
Autoantibodies with statistically significant differences (p < 0.05, FDR < 0.2) according to antibiotic exposure: (a) baseline; (b) 6 weeks.
Figure 2
Figure 2
Autoantibodies with statistically significant differences (p < 0.05, FDR < 0.2) according to antibiotic exposure: (a) baseline; (b) 6 weeks.
Figure 3
Figure 3
Heatmaps of antibodies with statistically significant differences (p < 0.05) according to antibiotic exposure: (a) Z–Score Baseline antibodies; (b) Z–Score 6 week antibodies.
Figure 3
Figure 3
Heatmaps of antibodies with statistically significant differences (p < 0.05) according to antibiotic exposure: (a) Z–Score Baseline antibodies; (b) Z–Score 6 week antibodies.
Figure 4
Figure 4
Best radiographic response according to antibiotic exposure in non-small cell lung cancer cases. (a) any antibiotic exposure versus no antibiotic exposure (p = 0.09); (b) antibiotic exposure pre-ICI initiation (p = 0.74); (c) antibiotic exposure post-ICI initiation (p = 0.02).
Figure 5
Figure 5
Systemic immune parameters with significant differences (p < 0.05 and FDR < 0.2) according to antibiotic exposure before ICI initiation in non-small cell lung cancer cases. (A) 6 weeks; (B) 6 weeks/baseline.
Figure 5
Figure 5
Systemic immune parameters with significant differences (p < 0.05 and FDR < 0.2) according to antibiotic exposure before ICI initiation in non-small cell lung cancer cases. (A) 6 weeks; (B) 6 weeks/baseline.
See this image and copyright information in PMC

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