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

Abstract

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.

Modulation of Anti-Tumour Immune Responses by Probiotic Bacteria

“…In another study by Mendes et al [105] using AOM/DSS-induced carcinogenesis in mice, a mixture of L. acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum led to a 40% reduction of tumour incidence, as well as lower levels of TNF-α and more IL-10 in the colon [105]. Recently, L. acidophilus has been found not only to attenuate weight loss caused by anti-CTL-4 antibodies but also to enhance the activity of immunotherapy [106]. This observation was associated with accumulation of CD8+ and effector memory (CD44+CD8+CD62+) T cells in the tumour.…”

Gut Microbiota Manipulation as a Tool for Colorectal Cancer Management: Recent Advances in Its Use for Therapeutic Purposes

“…Lastly, the combined administration significantly inhibited the abnormal increase in the relative abundance of Proteobacteria and partly counterbalanced CRC-induced dysbiosis in mice. Thus, CTLA-4 blocking antibodies in combination with the present lysates may be of importance for the development of new therapeutic strategies against CRC to be tested in clinical trials [ 144 ]. The postbiotic field is as yet a highly unknown area, considering that the number and diversity of bacterial metabolites are vast.…”

Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation—A Special Reference to Colorectal Cancer

“…In mouse colon cancer models, anti-CTLA-4 ICI in combination with Lactobacillus acidophilus lysates improved antitumor immune response through the increase of infiltrated T cells in the tumor microenvironment. L. acidophilus lysates also improved homeostasis in these mice [ 16 ]. Moreover, Xu et al, demonstrated that gut microbiota influences the efficacy of anti-PD-1 in MMR-proficient CRC through the glycerolphospholipid metabolic pathway.…”

“…Dysbiosis and microbial translocation have been associated with many health disorders, including inflammations, autoimmune disorders and precancerous or cancerous lesions [ 6 ]. It has already been demonstrated that gut microbiota, as an immunomodulator and a modulator of metabolism, could affect the efficacy of immunotherapy in cancer patients [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”