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

In the citing paper

“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].”

In the citing paper

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

In the citing paper

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

In the citing paper

“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).”

In the citing paper

“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 .”

In the citing paper

“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] .”

In the citing paper

“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 .”

In the citing paper

“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 the citing paper

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

In the citing paper

“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 the citing paper

“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.”

In the citing paper

“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.”

In the citing paper

“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 ).”

In the citing paper

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

In the citing paper

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

In the citing paper

“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.”

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

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

In the citing paper

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

In the citing paper

“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.”

In the citing paper

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

In the citing paper

“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.”

In the citing paper

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

In the citing paper

“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.”

In the citing paper

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

In the citing paper

“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.”

In the citing paper

“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”

In the citing paper

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

In the citing paper

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

In the citing paper

“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.”

In the citing paper

“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).”

In the citing paper

“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.”

In the citing paper

“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).”

In the citing paper

“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.”

In the citing paper

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

In the citing paper

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

In the citing paper

“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].”

In the citing paper

“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”

In the citing paper

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

In the citing paper

“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 the citing paper

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

In the citing paper

“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].”

In the citing paper

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

In the citing paper

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

In the citing paper

“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).”

In the citing paper

“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.”

In the citing paper

“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).”

In the citing paper

“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.”

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

“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.”

In the citing paper

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

In the citing paper

“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”

In the citing paper

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

In the citing paper

“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”

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

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

In the citing paper

“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.”

In the citing paper

“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”

In the citing paper

“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”

In the citing paper

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

In the citing paper

“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”

In the citing paper

“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 the citing paper

“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”

In the citing paper

“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 the citing paper

“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).”

In the citing paper

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

In the citing paper

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

In the citing paper

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

In the citing paper

“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.”

In the citing paper

“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.”

In the citing paper

“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.”

In the citing paper

“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.”

In the citing paper

“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.”

In the citing paper

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

In the citing paper

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

In the citing paper

“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).”

In the citing paper

“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).”

In the citing paper

“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 the citing paper

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