Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model

• Published in: Scientific reports Vol. 9; no. 1; p. 20128
• Main Authors: Zhuo, Qian, Yu, Bohai, Zhou, Jing, Zhang, Jingyun, Zhang, Runling, Xie, Jingyan, Wang, Qingling, Zhao, Shuli
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.12.2019; Nature Publishing Group
• Subjects: 631/67/2195; 64/60; 692/4028/67/1059/2325; 82/51; 96/31; Animal models; Animals; Antibodies, Blocking - pharmacology; Antineoplastic Agents, Immunological - pharmacology; Antitumor activity; Azoxymethane; Blocking antibodies; Body weight; Cancer; CD25 antigen; CD4 antigen; CD44 antigen; CD8 antigen; Cell Line, Tumor; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Complex Mixtures - chemistry; Complex Mixtures - pharmacology; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 protein; Cytotoxicity; Dextran; Dextran sulfate; Disease Models, Animal; Drinking water; Drug Synergism; Dysbacteriosis; Effector cells; Fecal microflora; Foxp3 protein; Gastrointestinal Microbiome; Humanities and Social Sciences; Humans; Immune response; Immunity; Immunoglobulin G - pharmacology; Immunological memory; Immunomodulation - drug effects; Immunotherapy; Interleukin 10; Intestinal microflora; L-selectin; Lactobacillus acidophilus; Lactobacillus acidophilus - metabolism; Lymphocytes T; Male; Mice; Monoclonal antibodies; multidisciplinary; Protective Agents - chemistry; Protective Agents - pharmacology; RAW 264.7 Cells; Relative abundance; Science; Science (multidisciplinary); T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Microenvironment; Xenograft Model Antitumor Assays; Yogurt
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-56661-y

Previous reports have suggested that many gut microbiomes were associated with the development of colorectal cancer (CRC), and could modulate response to numerous forms of cancer therapy, including checkpoint blockade immunotherapy. Here we evaluated the protective efficacy of Lactobacillus acidophilus (L. acidophilus) cell lysates combined with an anti-CTL antigen-4 blocking antibody (CTLA-4 mAb) in syngeneic BALB/c mice CRC models induce by a single intraperitoneal injection of 10 mg/kg azoxymethane (AOM), followed by three cycles of 2% dextran sulfate sodium (DSS) in drinking water. In contrast to CTLA-4 mAb monotherapy, L. acidophilus lysates could attenuate the loss of body weight and the combined administration significantly protected mice against CRC development, which suggested that the lysates enhanced antitumor activity of CTLA-4 mAb in model mice. The enhanced efficacy was associated with the increased CD8 + T cell, increased effector memory T cells (CD44 + CD8 + CD62L+), decreased Treg (CD4 + CD25 + Foxp3+) and M2 macrophages (F4/80 + CD206+) in the tumor microenvironment. In addition, our results revealed that L. acidophilus lysates had an immunomodulatory effect through inhibition the M2 polarization and the IL-10 expressed levels of LPS-activated Raw264.7 macrophages. Finally, the 16S rRNA gene sequencing of fecal microbiota demonstrated that the combined administration significantly inhibited the abnormal increase in the relative abundance of proteobacteria and partly counterbalance CRC-induced dysbiosis in model mice. Overall, these data support promising clinical possibilities of L. acidophilus lysates with CTLA-4 mAb in cancer patients and the hypothesis that probiotics help shape the anticancer immune response.