Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

In mice receiving anti-CTLA-4 immunotherapy, antitumor immunity was dependent on the presence of specific Bacteroides species.

“In mice receiving anti-CTLA-4 immunotherapy, antitumor immunity was dependent on the presence of specific Bacteroides species [7].”

Bacteroides fragilis enhanced the antitumor effect of CTLA-4 blockade by triggering DC maturation and stimulating IL-12-dependent Th1 cell immune responses.

“Bacteroides fragilis enhanced the antitumor effect of CTLA-4 blockade by triggering DC maturation and stimulating IL-12-dependent Th1 cell immune responses [17].”

The gut microbiota can modulate antitumor immunity and affect the efficacy of cancer immunotherapies, especially immune checkpoint inhibitors (ICIs).

“Currently, several lines of evidence from preclinical to clinical research have gradually established that the gut microbiota can modulate antitumor immunity and affect the efficacy of cancer immunotherapies, especially immune checkpoint inhibitors (ICIs).”

Mouse models have verified that Bifidobacteria, Bacteroides fragilis, and Burkholderia cepacia can ameliorate intestinal immunopathology in the context of anti-CTLA-4 therapy.

“Mouse models have verified that Bifidobacteria, Bacteroides fragilis, and Burkholderia cepacia can ameliorate intestinal immunopathology in the context of anti-CTLA-4 therapy [17, 125, 126].”

Primary responses to anti-PD-1/PD-L1 antibodies in epithelial tumours and melanoma can be partly attributed to the taxonomic composition of the gut microbial ecosystem.

“Supporting this contention, we and others reported that primary responses to anti-PD-1/ PD-L1 antibodies in patients with epithelial tumours and melanoma could, at least in part, be attributed to the taxonomic composition of the gut microbial ecosystem 18,20,25 .”

Antibiotics given before immune checkpoint inhibitor initiation reduce clinical benefit across several cancer types.

“Similarly, antibiotics (ATB) prior to ICI initiation drastically reduced the clinical benefit in several cohorts of patients across various cancer types (melanoma, advanced NSCLC, renal cell carcinoma (RCC), and urothelial cancer) 18,[20][21][22] .”

A diverse microbiota and the presence of specific bacteria such as Akkermansia muciniphila, Ruminococcus, or Bifidobacterium are associated with improved clinical response to immune checkpoint inhibitors and increased systemic immune tone.

“A diverse microbiota and the presence of specific bacteria such as Akkermansia muciniphila, Ruminococcus or Bifidobacterium genera were associated with improved clinical response to ICI, correlating with increased systemic immune tonus 18,20,25 .”

These transcriptomic results support the possibility that Akk could promote the elicitation or recirculation of Th1 cells into the tumor microenvironment, as previously shown in mouse models.

“These results support the possibility that Akk could promote the elicitation or recirculation of Th1 cells into the tumor microenvironment, as previously shown in mouse models 18,19 .”

In a prior subgroup of 60 NSCLC patients, Akk was overrepresented among those with progression-free survival greater than 3 months.

“Akk was also overrepresented in patients with progression free-survival (PFS) > 3 months, when analyzing a subgroup of 60 patients with NSCLC 18 .”

In a prior study of 100 refractory NSCLC or RCC patients receiving second- or third-line anti-PD-1 antibodies, Akk prevalence was higher in patients with partial response or stable disease than in those with progressive disease (61% versus 34%, p=0.007).

“We previously reported the stool metagenomic profiling of 100 patients diagnosed with refractory NSCLC or RCC receiving second or third line anti-PD-1 antibodies, concluding that the prevalence of A. muciniphila (Akk) was increased in patients presenting partial response or stable disease, as compared with patients in progressive disease (61 versus 34% respectively, p=0.007) 18 .”

In specific-pathogen-free eubiotic mice, MCA-205 fibrosarcomas are sensitive to anti-PD-1 antibody.

“We used MCA-205 fibrosarcomas because it is normally -in SPF eubiotic mice-sensitive to anti-PD-1 Ab and has been used as a reference mouse model in our previous avatar experiments reported in 18 and 37 , both papers showing that results obtained with MCA-205 were recapitulated in orthotopic TC1 lung cancer or RENCA RENal CArcinoma models, respectively.”

These results expand previous observations in smaller NSCLC cohorts and provide evidence that gut microbiome diversity and composition, specifically the relative abundance of Akk, offer relevant information to predict survival of NSCLC patients amenable to immune checkpoint inhibitors.

“These results expand on previous observations that have been made in smaller cohorts of patients with NSCLC 18,41 and provide evidence that gut microbiome diversity and composition, specifically the relative abundance of Akk, offer relevant information to predict survival of patients with NSCLC amenable to ICI.”

Preclinical data suggest that Akk can therapeutically bypass resistance to anti-PD-1 blockade conferred by fecal microbiota transplantation lacking endogenous Akk.

“Here, we provide preclinical data suggesting that Akk could therapeutically bypass the resistance to anti-PD-1 blockade conferred by FMT bereft of endogenous Akk (Extended Figure 6 and 17,18 ).”

The 60 patients with NSCLC already described in a previous report were excluded from the principal analysis.

“Of note, the 60 patients with NSCLC already described in our previous report 18 were excluded from the principal analysis.”

The gut microbiome can determine patient treatment outcomes for immune checkpoint inhibition (ICI) therapy.

“For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes.”

Members of the gut microbiota enhance the anti-tumor efficacy of PD-1 and CTLA4 blockade therapy.

“Recently, several studies have demonstrated that members of the gut microbiota are able to enhance the anti-tumor efficacy of PD-1 and CTLA4 blockade therapy6,7.”

The gut microbiota is associated with the efficacy of anti-CTLA4, anti-PD-1, and anti-PD-L1 treatment.

“Recently, the gut microbiota has emerged as a potent new factor associated with the efficacy of anti–CTLA4, anti–PD-1, and anti–PD-L1 treatment (8-14).”

TH1 responses to B. fragilis and A. muciniphila were associated with response to ipilimumab in melanoma and to anti-PD-1 in RCC or NSCLC, respectively.

“These include TH1 immune responses directed at B. fragilis and A. muciniphila were associated with responses to the anti-CTLA4 antibody ipilimumab in patients with melanoma125 and to anti-PD-1 antibodies in patients with RCC or NSCLC, respectively42 (Table 1).”

These results confirm previous observations of biphasic effects for the Bacteroides genus dependent on the specific treatment agent(s) used.

“These results confirm previous observations of biphasic effects for the Bacteroides genus dependent on the specific treatment agent(s) used9,40,41.”

The gut microbiome functions as a tumor-extrinsic biomarker that predicts response to immune checkpoint blockade.

“The intestinal microbiome has emerged as a tumor-extrinsic predictive biomarker to immune checkpoint blockade (ICB)1–6.”

In mouse models, certain gut commensals mediate the efficacy of anticancer therapies including chemotherapy, radiotherapy, adoptive T cell transfer, intratumoral CpG-oligonucleotides, and immune checkpoint inhibitors.

“In mouse models, certain gut commensals mediate efficacy of anticancer therapies, including chemotherapy, radiotherapy, and immunotherapies such as adoptive T cell transfer, intratumoral CpG-oligonucleotides, and ICIs.”

During CTLA-4 blockade in various cancers, Bacteroides fragilis triggers TLR2-4-dependent interleukin-12 release that is associated with anticancer effects.

“During CTLA-4 blockade in various cancers, Bacteroides fragilis triggers TLR2–4-dependent interleukin (IL)-12 release that is associated with anticancer effects.”

Exposures including medications such as antibiotics and proton pump inhibitors, and diet that shape the microbiota, are associated with ICI responses in patient cohorts and preclinical models.

“Second, exposures including medications, especially antibiotics and proton pump inhibitors, and diet that shape the microbiota are associated with ICI responses in patient cohorts and preclinical models.”

Microbiota in the gut and in tumours can influence cancer patient survival and treatment response.

“as the gut and tumour microbiota can affect the survival of patients with cancer and their responses to therapy8,14,40–42,50”

The role of the gut microbiome in modulating tumor responses to immunotherapy in melanoma, non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma has received increased attention across a series of studies.

“The role of the gut microbiome in modulating tumor responses to immunotherapy in melanoma [5–7], non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma [6, 8] has received increased attention across a series of studies in recent years.”

Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade.

“On the contrary, tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade (180).”

In mice and patients, T cell responses specific for Bacteroides species, such as thetaiotaomicron or fragilis, were associated with the efficacy of CTLA-4 blockade.

“Moreover, in mice and patients, T cell responses specific for Bacteroides species, such as thetaiotaomicron or fragilis were associated with the efficacy of CTLA-4 blockade.”

Specific gut bacteria, including Bacteroides fragilis, Bacteroides thetaiotaomicron, Bifidobacterium, Akkermansia muciniphila and Faecalibacterium spp., have favourable responses to cancer immunotherapy in preclinical tumour models and patients with cancer.

“Such as Bacteroides fragilis, Bacteroides thetaiotaomicron, Bifidobacterium, Akkermansia muciniphila and Faecalibacterium spp. have been shown to have favourable responses to cancer immunotherapy in both preclinical tumour models and patients with cancer.12–15”

Bacteroides spp. have a protective effect on gastrointestinal toxicity during CTLA-4 mAb treatment.

“Bacteroides spp. have a protective effect on gastrointestinal toxicity during CTLA-4 mAb treatment.13”

The genus Bacteroides enhances the antitumour effect and alleviates gastrointestinal toxicity in melanoma patients treated with CTLA-4 blockade.

“The genus Bacteroides enhance the antitumour effect and alleviate the gastrointestinal toxicity in melanoma patients treated with CTLA-4 blockade.13”

Anti-CTLA-4 treatment is ineffective in mice reared under sterile conditions.

“Anti-CTLA-4 treatment was found to be ineffective in mice reared under sterile conditions and to induce a shift in the gut flora of conventionally reared mice.”

Presence of certain bacterial strains, particularly Bacteroides fragilis, promoted Th1 polarization and was associated with improved anti-tumor immune response in animals.

“Further experiments showed that the presence of certain bacterial strains, in particular Bacteroides fragilis, promoted Th1 polarization in the animals and was associated with an improved anti-tumor immune response (97).”

Anti-CTLA-4 treatment induces a shift in the gut flora of conventionally reared mice.

“Anti-CTLA-4 treatment was found to be ineffective in mice reared under sterile conditions and to induce a shift in the gut flora of conventionally reared mice.”

Administration of B. fragilis to sterile mice treated with anti-CTLA-4 resulted in reduced tumor growth, most likely by inducing a favorable shift toward Th1 responses.

“In a similar study, administration of B. fragilis to sterile mice treated with anti-CTLA-4 resulted in reduced tumor growth, most likely by inducing a favorable shift toward Th1 responses (97).”

Enrichment of specific gut commensals, such as Bifidobacterium and Ruminococcaceae, had a significant positive correlation with CD8+ T cell infiltration in the tumor bed or tumor-draining lymph node.

“Analysis of fecal samples revealed that the enrichment of specific gut commensals, such as Bifidobacterium [32] and Ruminococcaceae [33], had a significant positive correlation with CD8+T cell infiltration in the tumor bed or tumor-draining lymph node.”

Both Bacteroides fragilis and Bifidobacterium promote the activation and maturation of dendritic cells (DCs).

“Both Bacteroides fragilis [31] and Bifidobacterium [32] were reported to promote the activation and maturation of DCs.”

Bifidobacterium is a positive regulator of therapeutic response.

“Further analysis identified Bifidobacterium as a positive regulator of therapeutic response [32].”

Mice with different commensal microbes exhibited difference in melanoma growth rate and response to PD-L1 blockade, which could be eliminated by cohousing and fecal FMT.

“mice with different commensal microbes exhibited difference in melanoma growth rate and response to PD-L1 blockade, which could be eliminated by cohousing and fecal FMT [32].”

Bacteroides fragilis and certain Akkermansia species induce IL-12-dependent TH1 responses during CTLA4 or PD-1 blockade.

“B. fragilis and some Akkermansia species drive IL-12-dependent T H 1 responses in the context of CTLA4 or PD-1 blockade 22,48”

Adjuvant signals from microbial molecules that engage host immune-cell pattern recognition receptors mediate gut microbiota effects on extraintestinal tumors.

“adjuvant signals mediated by microbial-associated molecular patterns acting on pattern recognition receptors expressed on host immune cells 30,48,49”

Microbiota-derived adjuvant signals, including lipopolysaccharide and surface proteins such as Amuc_1100 on A. muciniphila, act on Toll-like receptors TLR4 and TLR2 respectively and thereby raise immune tonus.

“Adjuvant signals produced by the microbiota include lipopolysaccharide (LPS) and specific surface proteins (such as Amuc_1100 present on the surface of A. muciniphila62 ) that act on Toll-like receptors such as TLR4 and TLR2, respectively, thus increasing the immune tonus.”

In oncology, converging findings demonstrate the negative impact of ATB-induced dysbiosis in mice.

“In oncology, converging findings demonstrate the negative impact of ATBinduced dysbiosis in mice.”

ATB-based conditioning of tumor-bearing mice blunts the efficacy of PD-1 or PD-1 + CTLA-4 blockade, suggesting a causal link between ATB and primary resistance to ICI.

“It is noteworthy that ATB-based conditionning of tumor bearing mice blunts the efficacy of PD-1 or PD-1 þ CTLA-4 blockade in otherwise 'normal' animals, suggesting a causal link between ATB and primary resistance to ICI and immunogenic chemotherapy [9,10,30,31].”

The microbiome influences tumor immunity and the response to immune checkpoint inhibitors.

“The microbiome has been described to majorly impact tumor immunity and response to ICI10–17”

Other groups have reported distinct bacterial signatures in patients who develop colitis associated with ICI.

“Other groups have also demonstrated differential bacterial signatures in the gut microbiome of patients who develop ICI-associated colitis14–16”

CTLA-4 blockade causes intraepithelial lymphocytes to damage ileal epithelium, promoting Bacteroides fragilis and Burkholderiales accumulation that activates IL-12-producing dendritic cells and TH1 responses.

“Upon CTLA-4 blockade, intraepithelial lymphocytes damage ileal epithelial cells, stimulating the accumulation of Bacteroides fragilis and Burkholderiales spp., activating IL-12-producing dendritic cells ( D C s )a n dTh e l p e r1( T H 1) immune responses (13).”

16S rRNA gene amplicon and shotgun DNA sequencing of patient stool identified bacterial subsets more abundant in responders than nonresponders.

“16S ribosomal RNA (rRNA)-based sequencing of gene amplicons and shotgun DNA sequencing of patient stool samples have identified subsets of bacteria more abundant in responding versus nonresponding patients.”

Several anticancer treatments-metronomic cyclophosphamide, platinum chemotherapy, TLR9 agonist plus anti-IL-10R, and anti-CTLA-4 and/or anti-PD-1/PD-L1-lose efficacy when gut microbiota are absent or altered.

“Soon after, it was observed that several anticancer treatment modalities showed reduced therapeutic effects in germ-free mice as well as in mice treated with broad-spectrum antibiotics (11)(12)(13)(14), or in mice lacking specific immunepotentiating bacterial species originating from different vendors (15).”

Health-associated or immunogenic bacteria were more abundant in responding patients.

“Given these considerations, it is perhaps even more striking that bacteria generally associated with health (such as Clostridiales, Ruminococcacae, Faecalibacterium spp., Akkermansia muciniphila, B. fragilis,a n dBifidobacteria) (13, 14, 18-20) or immunogenicity (Enterococci, Collinsella, and Alistipes)( 11, 13, 14, 20) were found to be abundant in responding patients.”

Microbial stimulation of anticancer memory TH1/Tc1 responses only partly depends on TLR2/TLR4 during cyclophosphamide or CTLA-4 blockade.

“However, the microbial stimulation of anticancer memory T H 1/Tc1 cell responses only partially rely on TLR2/TLR4 in the context of treatments with cyclophosphamide (16)o rC T L A -4b l o c k a d e ( 13).”

Dendritic cells exposed to B. fragilis or A. muciniphila induce systemic IL-12-dependent TH1/Tc1 responses that benefit tumors treated with anti-CTLA-4 or anti-PD-1/PD-L1.

“In terms of effects on pattern recognition receptors, DCs exposed to microbes (such as B. fragilis or A. muciniphila) associated with anticancer properties induce systemic IL-12-dependent T H 1/Tc1 immune responses beneficial against tumors treated with antibody to CTLA-4 (13)orPD-1/PD-L1(14).”

The effect depended on distinct Bacteroides species in ipilimumab-treated melanoma, partly on Faecalibacterium in melanoma, and on Verrucomicrobiaceae/A. muciniphila in PD-1 inhibitor-treated lung cancer.

“This effect depended on distinct Bacteroides species in melanoma treated with ipilimumab (13) and at least partly on Faecalibacterium (19)inmelanomaandonVerrucomicrobiacae [more specifically, A. muciniphila (14)] in lung cancer patients treated with the PD-1 inhibitors pembrolizumab or nivolumab.”

Gavage with B. fragilis and Burkholderia cepacia reduced anti-CTLA-4-induced colitis severity in mice.

“Accordingly, B. fragilis and Burkholderia cepacia administered via gavage to mice reduced the severity of colitis induced by mAb to CTLA-4 (13,22).”

FMT from immune checkpoint blockade responders transferred a responder phenotype to mice, while nonresponder feces tended to transfer nonresponsiveness.

“Notably, fecal microbial transplantation (FMT) o ff e c e sf r o mp a t i e n t s( w h os h o w e dc l i n i c a lr esponse to immune checkpoint blockade) transferred a”

Antibiotics (except vancomycin), proton pump inhibitors, and probiotics may alter the taxonomic composition of the intestinal microbiota, resulting in resistance to immunotherapy.

“Of note, antibiotics (except vancomycin),4”

Antibiotics negatively affect treatment with immune checkpoint blockade, likely by reducing gut microbial diversity.

“multiple studies demonstrated the negative impact of antibiotics in the context of treatment with ICB, likely due to their detrimental impact on gut microbial diversity”

Enterococcus hirae, Bacteroides fragilis, and Eubacterium sp. AM28-29 have been linked to improved responses in preclinical and clinical settings, often through mechanisms such as dendritic cell maturation and cytokine production including IL-12.

“Other bacteria like Enterococcus hirae (Viaud et al., 2013), Bacteroides fragilis (Vétizou et al., 2015), and Eubacterium sp. AM28-29 (Thomas et al., 2023) have been linked to improved responses in preclinical and clinical settings, often through mechanisms such as dendritic cell maturation and cytokine production (including IL-12).”

The role of FMT in boosting ICB response was first demonstrated in mice when the gut microbiome's influence on ICB success was recognized.

“More recently, its role in boosting ICB response was first demonstrated in mice when the gut microbiome’s influence on ICB success was suddenly recognized (Routy et al., 2018b, 2023; Vétizou et al., 2015).”

B. fragilis can restore anti-CTLA-4 efficacy after antibiotic treatment or in germ-free mice.

“For example, mouse studies have shown that B. fragilis can restore anti-CTLA-4 efficacy after antibiotic treatment or in germ-free mice (Vétizou et al., 2015).”

Immune responses to CTLA-4 blockade and cyclophosphamide are associated with distinct gut microbiome configurations.

“Immune responses to other anticancer treatments, including CTLA-4 blockade194 and cyclophosphamide,195 were also associated with distinct gut microbiome configurations.”

Initial evidence on gut microbiota and immunotherapy came from mouse models, and many findings were later validated in patient cohorts receiving immune checkpoint blockade.

“Important initial insights came from murine models (Sivan et al., 2015, Vetizou et al., 2015), and many of these findings have now been validated in several patient cohorts treated with immunotherapy, specifically immune checkpoint blockade.”

Oral feeding of Bacteroides fragilis with either Bacteroides thetaiotaomicron or Burkholderia cepacia enhanced anti-CTLA-4 therapy by eliciting a Th1 response and maturing intra-tumoral dendritic cells.

“oral feeding with Bacteroides fragilis in combination with either Bacteroides thetaiotaomicron or Burkholderia cepacia augmented the action of anti-CTLA-4 therapy by eliciting a Th1 response in the lymph nodes and facilitating the maturation of intra-tumoral dendritic cells”

FMT from patients with dominant Bacteroides species improved tumor control compared with FMT from patients with distinct Bacteroides or Prevotella species.

“FMT from patients having dominant Bacteroides species in their gut resulted in improved tumor control compared to FMT from patients with distinct Bacteroides or Prevotella species”

Anti-CTLA-4 efficacy is markedly reduced in germ-free mice and in specific-pathogen-free mice given broad-spectrum antibiotics.

“The efficacy of anti-CTLA-4 therapy was markedly reduced in GF mice and SPF mice with broad-spectrum antibiotics.”

In anti-CTLA-4-treated mice, oral gavage of Bacteroides fragilis and Burkholderia cepacia improved toxicity scores.

“Pre- clinical models have demonstrated an improvement in toxicity scores in anti-CTLA-4-treated mice with oral gavage of Bacteroides fragilis and Burkholderia cepacia”

The composition of the gut microbiota can influence response to CTLA-4 and PD-1 immune checkpoint inhibitors in mice.

“demonstrating that the composition of the gut microbiota could influence the response to immune checkpoint inhibitors targeting the cytotoxic T lymphocyte antigen-4 (CTLA-4) and the programmed death receptor-1 (PD-1)”

In mice, anti-CTLA-4 therapy changes gut microbiota abundance, increasing Bacteroidales and Burkholderiales and decreasing Clostridiales.

“notable changes in the abundance of gut microbiota in mice were seen following anti- CTLA-4 therapy, with a relative increase in Bacteroidales and Burkholderiales, and a decrease in Clostridiales”

Fecal transplants from patients who benefited from anti-CTLA-4 favored growth of B. fragilis, linking this species with improved response.

“In addition, fecal transplants from patients who benefitted clinically from anti-CTLA-4 therapy favored the growth of B. fragilis, linking this species with improved response.”

In preclinical models, anti-CTLA-4 response depends on Bacteroides species; germfree or antibiotic-treated mice do not respond, but response is rescued by B. fragilis gavage.

“For example, in preclinical models, the therapeutic response to anti-CTLA-4 therapy was found to be dependent on Bacteroides species, as germfree mice or antibiotic-treated mice did not respond to anti-CTLA-4, but response was rescued through gavage of Bacteroides fragilis (99).”

Mice transplanted with stool from patients with bacteroides-rich microbiota respond better to CTLA4 inhibitor treatment.

“For example, mice transplanted with liquefied and filtered stool from patients with bacteroides‐rich microbiota population respond better to CTLA4 inhibitor treatment [431].”

In GF or ATB-treated mice, activation of effector CD4+ T cells and TILs elicited by CTLA-4 blockade was considerably dampened.

“In GF or ATB-treated mice, activation of effector CD4+ T cells and TILs elicited by CTLA-4 blockade was considerably dampened.”

A combination of antibiotics or imipenem alone destroyed the function of CTLA-4 inhibitors against the tumor.

“A combination of ATBs (ampicillin, colistin, and streptomycin) or imipenem alone destroyed the function of CTLA-4 inhibitors against the tumor.”

Recolonization of ATB-treated or GF mice with commensal bacteria, such as Bacteroides and Burkholderia genres, could restore the CTLA-4 blockade-mediated anticancer responses.

“Moreover, recolonization of ATB-treated or GF mice with commensal bacteria, such as Bacteroides and Burkholderia genres, could restore the CTLA-4 blockade-mediated anticancer responses.”

Management of gut microbiome elicits modification of TME and turns on a switch for the development of resistance to immune therapy, which enables tumor cells to escape immune surveillance.

“In other words, management of gut microbiome elicits modification of TME and turns on a switch for the development of resistance to immune therapy, which enables tumor cells to escape immune surveillance.”

CTLA-4 blocking therapy could reverse the gut bacteria repertoire, causing a decrease in beneficial bacteria and an increase in bacteria that blunt the response to ipilimumab.

“Interestingly, it was discovered that CTLA-4 blocking therapy could reverse the gut bacteria repertoire, causing a decrease in beneficial bacteria and an increase in bacteria that blunt the response to ipilimumab.”

Dietary supplements with Bacteroides fragilis induced Th1 immune responses in the tumor-draining lymph nodes, prompted the maturation of DCs in the TME, and facilitated the restoration of the clinical response to CTLA-4 blockade.

“In fact, dietary supplements with Bacteroides fragilis induced Th1 immune responses in the tumor-draining lymph nodes prompted the maturation of DCs in the TME and facilitated the restoration of the clinical response to CTLA-4 blockade.”

CTLA-4 blocking therapy was effective against sarcoma, melanoma, and colon cancer in SPF mice but not in GF mice.

“In this study, CTLA-4 blocking therapy was found to be effective against sarcoma, melanoma, and colon cancer in SPF mice but not in GF mice.”

Gut microbiota might be indispensable for the antitumor efficacy of anti-CTLA-4 treatment.

“These preliminary results showed that gut microbiota might be indispensable for the antitumor efficacy of anti-CTLA-4 treatment.”

Production of cytokines may be one mechanism used by the gut microbiome to alter resistance to therapy.

“Therefore, the production of cytokines may be one of the mechanisms used by the gut microbiome to alter resistance to therapy.”

Gut bacteria that significantly prolong PFS show a preserved cytokine response to PD-1-target treatment, whereas antibiotics decrease the level of cytokines in TME.

“The gut bacteria that significantly prolong PFS show a preserved cytokine response to PD-1-target treatment, whereas antibiotics have been demonstrated to decrease the level of cytokines in TME (67).”

Orally feeding B. fragilis induced Th1 immune response in tumor-draining lymph nodes and catalyzed maturation of DCs in the TME, facilitating restoration of clinical response to CTLA-4 blockade.

“orally feeding B. fragilis induced Th1 immune response in the tumor-draining lymph nodes and catalyzed the maturation of DCs in the TME, facilitating the restoration of the clinical response to CTLA-4 blockade (67).”

The efficacy of anti-CTLA4 antibodies in reducing sarcoma tumor growth in mice is significantly increased when the gut microbiome is enriched in Bacteroides fragilis and Burkholderia cepacia.

“Vetizou et al. demonstrated that the efficacy of anti-CTLA4 antibodies in reducing sarcoma tumor growth in mice is significantly increased when the gut microbiome is enriched in Bacteroides fragilis and Burkholderia cepacia [175].”

In animals, oral gavage of Bacterioides fragilis and Burkholderia cepacia ameliorated immunotherapy-associated toxic side effects.

“In animals, oral gavage of Bacterioides fragilis and Burkholderia cepacia demonstrated an amelioration of such immunotherapy-associated toxic side effects [175].”