Impact of intestinal dysbiosis-related drugs on the efficacy of immune checkpoint inhibitors in clinical practice

Pérez-Ruiz, Elísabeth; Jimenez-Castro, Jeronimo; Berciano‐Guerrero, Miguel‐Ángel; Valdivia, Javier; Estalella-Mendoza, S.; Toscano, Fátima; Artacho, María Rodríguez de la Borbolla; Garrido-Siles, Margarita; Martínez-Bautista, María José; Roldán, Rosa Villatoro; Rivas‐Ruiz, Francisco; Nogales-Fernández, Esteban; Morales, Cristina; Pérez-Valderrama, Begoña; Cruz‐Merino, Luis de la; Rueda, Ángel Inoriza

doi:10.1007/s12094-020-02315-9

Cited by 12 publications

(12 citation statements)

References 31 publications

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“… 20 However, anti-PD-1 can cause immune-related adverse effects, especially in the patients with the dysbiosis of gut microbiota. 44 One of the most common toxicities is anti-PD-1-associated colitis. Here, histopathological analysis of colons confirmed that L. paracasei sh2020 administration might help to maintain intestinal homeostasis by modulating gut microbiota, which was a novel and promising strategy to mitigate the immune checkpoint inhibitor-associated colitis.…”

Section: Discussionmentioning

confidence: 99%

Lacticaseibacillus paracasei sh2020 induced antitumor immunity and synergized with anti-programmed cell death 1 to reduce tumor burden in mice

et al. 2022

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The gut microbiota was emerging as critical regulatory elements in shaping the outcome of cancer immunotherapy. However, the underlying mechanisms by which the gut commensal species enhance antitumor immunity remain largely unexplored. Here, we show that the gut microbiota from healthy individuals conferred considerable sensitivity to anti-PD-1 in the colorectal cancer (CRC) tumor-bearing mice, whereas gut microbiota from CRC patients failed to do so. By 16S rRNA gene sequencing, we identified Lactobacillus that was significantly increased in the mice with good response to anti-PD-1, and significantly correlated with anti-tumor immunity. After a series of screening, we isolated a novel Lacticaseibacillus strain, named L. paracasei sh2020. L. paracasei sh2020 showed the most notable anti-tumor immunity in the mice with gut dysbiosis. Mechanistically, the antitumor immune response elicited by L. paracasei sh2020 was dependent on CD8 + T cell. In vitro and in vivo studies revealed that L. paracasei sh2020 stimulation triggered the upregulated expression of CXCL10 in the tumors and subsequently enhanced CD8 + T cell recruitment. Meanwhile, the modulation of gut microbiota caused by L. paracasei sh2020 enhanced its antitumor effect and gut barrier function. Overall, our study offered novel insights into the mechanism by which gut microbiota shaped the outcome of cancer immunotherapy and, more importantly, the novel strain L. paracasei sh2020 might serve as an easy and effective way to promote anti-PD-1 effect in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Lacticaseibacillus paracasei sh2020 induced antitumor immunity and synergized with anti-programmed cell death 1 to reduce tumor burden in mice

et al. 2022

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“…Of note, preclinical models have shown that GM plays a fundamental role in initiation and progression of cancer, thus making it appealing as a therapeutic target that could change our daily clinical practice [ 58 ]. Changes in diet, use of antibiotics as well as other drugs, probiotics or lifestyle habits, impact the microbiome composition [ 36 ]. Therefore, the disease model has changed from a simplistic one to a more complex, intricate network of actors where the microbiome and the immune system may play a leading role in the response to treatments [ 59 ].…”

Section: Gut Microbiome and Cancermentioning

confidence: 99%

“…The immune reprogramming in TME has been established as one of the main targets of the microbiome, and not only by promoting these inflammatory responses, but also by inducing immunosuppressive phenotypes or even conducting anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), dietary supplements and impact of use of antibiotics and probiotics as predictors of response to ICI and other treatments [ 36 , 92 ]. It would also be appealing to understand the result of these interventions in patients treated with MAPK inhibitors to enhance therapeutic approaches.…”

Section: Gut Microbiome and Immune Systemmentioning

confidence: 99%

“…Although it is still not well-known nor understood, GM has been linked to various diseases, including diabetes mellitus, metabolic syndrome, autoimmune diseases and cancer [ 32 , 33 , 34 , 35 ]. Gut Microbiota has also been reported as a predictive biomarker of response to chemotherapy, radiotherapy, immunotherapy and targeted therapy [ 36 , 37 , 38 , 39 , 40 ]. It is known to be modified by certain drugs; for example, in patients treated with citalopram that present an enrichment of Enterobacteriaceae, or those using antibiotics or proton-pump inhibitors where Bacteroides are predominant.…”

Section: Introductionmentioning

confidence: 99%

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Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition

Guardamagna

Berciano‐Guerrero

Villaescusa-González

et al. 2022

IJMS

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Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy—BRAF/MEK inhibitors—have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM’s link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.

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“…After early encouraging reports showing that the use of anthracyclines such as doxorubicin, epirubicin or idarubicin to treat various tumor types resulted in the potentiation of the patient's anti-tumor immunity [133], and data from other studies showed that antibiotic treatment had no deleterious effects on the response of non-small cell lung carcinomas (NSCLC) to treatment with the immune checkpoint inhibitor (ICI) nivolumab [134,135], results from preclinical chemo-immunotherapy protocols combining cyclophosphamide chemotherapy with adoptive T-cell (ACT) immunotherapy, using a mouse model of B-cell lymphoma, demonstrated that prophylactic use of broad-spectrum antibiotics reduced the efficacy of cyclophosphamide and impaired the therapeutic effects of ACT [136]. Since then, most studies have reported negative effects of antibiotic exposure leading to diminished levels of efficacy of ICIs in immunotherapy protocols for the treatment of a variety of tumors, including lung tumors/NSCLC [137][138][139][140][141][142][143][144], advanced or metastatic renal cell carcinoma [137,141,142,144], urothelial carcinoma [141], and melanoma [141,143,144]. In addition, more recently, it has been reported that antibiotic use had a negative impact on the response of patients with locally advanced head-and-neck tumors to treatment protocols involving chemotherapy or radiotherapy [145].…”

Section: Antibiotics and Cancer Therapy Outcomesmentioning

confidence: 99%

A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives

Amadei

Notario

2020

Antibiotics

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Cancer is predominantly considered as an environmental disease caused by genetic or epigenetic alterations induced by exposure to extrinsic (e.g., carcinogens, pollutants, radiation) or intrinsic (e.g., metabolic, immune or genetic deficiencies). Over-exposure to antibiotics, which is favored by unregulated access as well as inappropriate prescriptions by physicians, is known to have led to serious health problems such as the rise of antibiotic resistance, in particular in poorly developed countries. In this review, the attention is focused on evaluating the effects of antibiotic exposure on cancer risk and on the outcome of cancer therapeutic protocols, either directly acting as extrinsic promoters, or indirectly, through interactions with the human gut microbiota. The preponderant evidence derived from information reported over the last 10 years confirms that antibiotic exposure tends to increase cancer risk and, unfortunately, that it reduces the efficacy of various forms of cancer therapy (e.g., chemo-, radio-, and immunotherapy alone or in combination). Alternatives to the current patterns of antibiotic use, such as introducing new antibiotics, bacteriophages or enzybiotics, and implementing dysbiosis-reducing microbiota modulatory strategies in oncology, are discussed. The information is in the end considered from the perspective of the most recent findings on the tumor-specific and intracellular location of the tumor microbiota, and of the most recent theories proposed to explain cancer etiology on the notion of regression of the eukaryotic cells and systems to stages characterized for a lack of coordination among their components of prokaryotic origin, which is promoted by injuries caused by environmental insults.

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Impact of intestinal dysbiosis-related drugs on the efficacy of immune checkpoint inhibitors in clinical practice

Cited by 12 publications

References 31 publications

Lacticaseibacillus paracasei sh2020 induced antitumor immunity and synergized with anti-programmed cell death 1 to reduce tumor burden in mice

Lacticaseibacillus paracasei sh2020 induced antitumor immunity and synergized with anti-programmed cell death 1 to reduce tumor burden in mice

Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition

A Significant Question in Cancer Risk and Therapy: Are Antibiotics Positive or Negative Effectors? Current Answers and Possible Alternatives

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