Association between Antibiotic Exposure and Systemic Immune Parameters in Cancer Patients Receiving Checkpoint Inhibitor Therapy
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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 and
David E. Gerber
1,2,4,*add
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1
Department of Internal Medicine, Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
2
Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3
School of Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4
Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
5
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
6
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
7
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally.
Cancers 2022, 14(5), 1327; https://doi.org/10.3390/cancers14051327
Submission received: 14 January 2022
/
Revised: 28 February 2022
/
Accepted: 2 March 2022
/
Published: 4 March 2022
(This article belongs to the Special Issue Immune Checkpoint Inhibitors in Cancer Therapy—How Can We Improve Clinical Benefits?)
Simple Summary
Patients treated with antibiotics have worse outcomes from cancer immunotherapy. While antibiotics are known to affect intestinal flora, it is not clear how they affect overall immune function. The aim of our study was to identify differences in immune parameters according to antibiotic exposure. Among 251 total patients, the 135 (54%) who received antibiotics had lower response rates and shorter survival. We identified significant differences in multiple antibodies according to antibiotic exposure, including antibodies specific for nucleolin, MDA5, c-reactive protein, LC1, heparin sulfate, Matrigel, and CENP.B. In lung cancer patients, antibiotics were associated with differences in IFN-γ, IL-8, and macrophage inflammatory protein cytokines. Administration of antibiotics to patients receiving cancer immunotherapy is associated with changes in circulating antibodies and cytokines, although it is not clear if antibiotics cause these differences. Given the frequency of antibiotic use in cancer populations and potentially detrimental effects on immunotherapy outcomes, more research in this area may guide patient management.
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
