Abdullah Hashmi, MD

Emerging research suggests a potential role of the gut microbiome in cancer development and in determining therapy efficacy. Research focusing on enhancing treatment efficacy by modulating the gut microbiome is ongoing.

In humans, the gut microbiota serves many functions. The normal gut microbiota metabolizes nutrients and drugs, maintains the gut mucosal barrier integrity, protects against pathogens, and trains and develops the immune system.

 The gut microbiome has been implicated in many human pathologies.

“In the past 5 years, the gut microbiome and its effect on the immune system have led to it becoming a source of biomarkers that can predict response to cancer therapy and potentially be modified as therapy itself,” said Karla Lee, SpR, a clinical research fellow and PhD candidate at King’s College, London, England, United Kingdom, during an interview with 

™. Lee’s area of study focuses on gut microbiota in oncology research.

The gut microbiome represents a new age of holistic cancer treatment. Whereas in the past, biomarkers to predict therapy response were tumor-centric and involved characterizing tumor mutational load, metabolism, and sensitivity to immune effectors, the gut microbiota is a new, nontumor-centric area with therapeutic potential.

“What makes the gut microbiome really exciting is that it is modifiable and in terms of treatment it is something patients can [affect] on their own to improve their odds of response to therapy,” said Jennifer Leigh McQuade, MD, an assistant professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center in Houston during an interview with 

It is important for clinicians to grasp how the gut microbiome may affect tumor progression. The gut microbiota consists of approximately 100 trillion microbes existing in a stable state that interact with the host immune system.

 Disruption of the stable commensal bacteria results in an unstable state of dysbiosis that may lead to tumorigenesis. Observational studies have shown bacteremia from S

 has been associated with an increased risk of developing colorectal cancer.

 Although mechanisms are still being understood, some pathogenic bacteria are thought to induce host DNA damage, cause oxidative stress damage, or inhibit host antitumor responses by acting on the tumor microenvironment.

In addition to its unique association with tumorigenesis, the gut microbiome’s interaction with intestinal epithelium affects host immunity and may thereby affect the tumor microenvironment. In animal models, mice lacking intestinal microbiota have severe defects in immunity, an absent mucous layer, altered IgA secretion (IgA blocks bacterial adherence to epithelial cells), and reduced size and functionality of Peyer patches and draining mesenteric lymph nodes.

“Given the important role of the gut microbiota in maintaining host immunity, it has been theorized that alterations of the gut microbiome can affect immune responses within the tumor microenvironment,” Lee said. Cancer cells manipulate and suppress immune cells to persist. In fact, development of immune checkpoint inhibitors (ICI) has changed cancer therapy by inhibiting tumoral immunosuppression within the tumor microenvironment and allowing effector cells to attack tumor cells.

 However, ICIs are not universally effective across all cancers.

“It is important to determine when ICIs are and are not effective,” said McQuade, whose focus of research is on dietary modulation of the microbiome for oncotherapy. Given its immunologic effects, exploration of the gut microbiome for biomarkers has allowed for identification of microbiome signatures that help determine when ICIs are effective.

 Characterization of the microbiome identifies features in those who do or do not respond to ICI therapy. In those situations, the microbiome can be modulated to create an environment for response to ICI therapy.

A recent study analyzing the intratumoral microbiome in patients with colorectal cancer identified an abundance of 

 in younger patients that was absent in elderly patients.

 Furthermore, younger patients had better overall survival (OS), suggesting that the presence of 

 has a role in determining clinical outcomes from colorectal cancer. Similarly, in patients with colorectal cancer, numbers of Fusobacterium nucleatum increase as cancer progresses.

 It has been shown that F nucleatum suppresses host lymphocytes and natural killer cells by binding to the inhibitory immune receptor TIGIT.

 “It has become clear that the gut microbiome has an important role to play in the etiology or treatment of many cancer subtypes,” Lee said. 

Not only is the microbiome associated with clinical outcomes, but it can also affect the efficacy of cancer therapies such as chemotherapy. F nucleatum has been associated with oxaliplatin chemotherapy resistance in patients with colorectal cancer.

 Also, lung tumor–bearing mice treated with cisplatin and gut microbiota–depleting antibiotics developed larger tumors and had poorer survival.

 However, certain bacteria may improve chemotherapy response. Cyclophosphamide therapy was improved when combined with commensal bacteria such as 

The combination converted naïve T cells to proinflammatory Th17 cells and ultimately improved cyclophosphamide efficacy.

“Similar to its effect on chemotherapy, the gut microbiota has also been shown to affect ICI efficacy,” McQuade said. The gut microbiota primes cells for an effective immune response. T cells are inhibited in the tumor microenvironment. Bacteria such as 

 produce metabolites like inosine, which helps to activate T cells that are normally restricted in the tumor microenvironment.

 Inosine supplementation enhanced the antitumor efficacy of ICI.

 “Sometimes we focus too much on who the bugs are as opposed to what they are doing,” said McQuade. 

Much research has focused on identifying microbiome biomarkers that affect ICI efficacy. Specific examples help to explain the association of the gut bacteria and metabolites with ICI efficacy.

In murine models, Sivan et al showed the efficacy of anti–PD-L1 antibodies in melanoma was improved in the presence of gut microbiome enriched with 

Bifidobacterium species are combined with anti–PD-L1 antibodies, there was enhanced CD8+ T-cell priming and accumulation in

the tumor microenvironment that inhibited melanoma growth. “Most research involves associations of microbiota with ICI efficacy. This study showed the potential for selected microbiota as therapy in conjunction with ICIs, giving microbiota manipulation practical value,” McQuade said. Moreover, it was shown that patients with melanoma treated with anti–PD-1/anti–PD-L1 ICI had lower OS and progression-free survival (PFS) when treated with antibiotics.

A study investigating phase 2 neoadjuvant trials of anti–PD-1/anti-CTLA-4 antibodies for melanoma, non–small cell lung cancer, and sarcoma saw that among all cancers, an abundance of Ruminococcus was higher in responders and had an increase in B-cell signatures not seen in patients with a low abundance of Ruminococcus.

 Several examples have shown that strains of bacteria are associated with ICI therapy outcomes and can potentially be used both to predict response to ICI therapy and in conjunction with therapy to improve patient outcomes.

Gut Microbiome Modulation Techniques for Enhanced ICI Response

“What is exciting about the microbiome is that it is inherently modifiable. We can’t change our germline genome or tumor genome, but we can change our gut microbiome. We are starting to see that microbiomodulation certainly holds promise,” McQuade said.

Microbiome modulation by supplementing bacteria and metabolites in patients who do not respond to ICI therapy has shown potential to inhibit cancer progression and augment the efficacy of immunotherapies.

 The administration of live bacterial specimens like 

 can influence anti-inflammatory cytokine levels, degrade carcinogens, activate phagocytes to eliminate early-stage cancer cells, and produce short chain fatty acids that affect cell death and proliferation.

Fecal microbiota transplantation (FMT) from PD-1 responders with favorable gut microbiome or from a young person with healthy gut microbiome could potentially be transplanted into PD-1–resistant patients. A phase 1 study (NCT03353402) assessed the safety and feasibility of anti–PD-1 refractory melanoma with reinduction of anti–PD-1 inhibitors after FMT. Of 10 patients, 3 responded (1 complete, 2 partial).

“These results, although only 30% efficacious, give meaning to microbiome manipulation and FMT therapy,” said McQuade. FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles.

 FMT studies show that the microbiome is modifiable and there is potential to overcome resistance with the prior immunotherapy. “These are very exciting results, although early studies,” stated Lee.

Similarly, a study showed that patients with cancer who responded to anti–PD-1 therapy were rich in Akkermansia. Replenishing those deficient in Akkermansia with FMT has shown an improvement in anti–PD-1 efficacy in previous nonresponders.

In patients with acute myeloid leukemia treated with intensive chemotherapy and antibiotics, a phase 2 study (NCT02928523) showed autologous fecal microbiota transfer was safe and effective to restore richness and diversity in the gut microbiome.

A recent study (NCT03829111) showed patients with renal cell carcinoma treated with either anti–CTLA-4/anti–PD-1 therapy alone or in conjunction with CBM588, a bifidogenic live bacterial product, had enhanced clinical outcomes. PFS was significantly longer in patients receiving ICI therapy with CBM588 than without (12.7 months vs 2.5 months, 

 = .001), without a significant difference in toxicity.

 “Larger studies are needed to elucidate the mechanism of action, but the results are promising,” noted Lee.

The use of antibiotics such as vancomycin to decrease harmful gram-positive bacteria but not affecting gram-negative bacteria such as 

 enhanced the efficacy of anti–CTLA-4 therapy.

This has led to bacteriophages designed to target only detrimental and pathogenic bacteria as another therapeutic strategy. In mouse models, a bacteriophage that killed 

 led to reduced immunosuppressive myeloid-derived suppressor cells in the tumor microenvironment and prolonged OS time when coupled with ICIs.

Although FMT has been the focus of therapy and bacteriophage research is ongoing, other mechanisms for microbiota modulation exist. A novel microbiome-derived therapeutic vaccine used in conjunction with ICI therapy in patients with adrenocortical carcinoma was safe and induced an immune response.

“I think that one massively neglected area in oncology is diet, and this is obviously very closely related to the gut microbiome in many ways. Diet is the most modifiable factor affecting the development and condition of the gut microbiome,” Lee said. Similarly, McQuade has focused her research on dietary manipulation for improved outcomes in cancer treatment.

“Patients with higher habitual consumption of fiber have improved response to immunotherapy,” McQuade noted. High fiber intake and elimination of animal fats can increase immune-promoting bacteria like 

 and decrease detrimental bacteria like Bacteroidales.

The daily use of probiotics is controversial. Probiotics may decrease biologic diversity in individuals and can alter cytokine profiles.

 For example, in colorectal cancer, treatment with 

 lactis led to an abundance of butyrate-producing bacteria within the tumor. Furthermore, pretreatment with a preoperative probiotic in patients with colorectal cancer altered cytokine profiles with lower numbers of cytokines assessed at time of mucosal resection, giving mixed results.

A major challenge with ICI treatment involves treatment-related toxicities leading to delays and discontinuation of treatment. One-third of all patients undergoing anti–CTLA-4 therapy experience intestinal inflammation. The combination of anti–CTLA-4 and anti–PD-1 blockade may result in high-grade toxicity requiring hospitalization in more than 50% of patients receiving treatment.

 “Anyone who has worked in immune oncology understands how devastating and unpredictable immune-related adverse events (irAEs) can be. I would love to see more gut microbiome studies that focus on toxicity,” Lee said.

Recently, in advanced gastric carcinoma, the gut microbiome was analyzed for predictors of anti–PD-1 induced toxicity in patients treated with nivolumab (Opdivo).

Arthrobacter was identified as a candidate marker for skin eruptions, as patients with high levels of Arthrobacter experienced this symptom more frequently. Single-nucleotide polymorphisms were also identified, including 

Patients treated with anti–CTLA-4 antibodies have shown, in preclinical models, oral gavage of 

 benefit in reducing irAEs and lessened toxicity scores.

In human cohorts, patients with melanoma treated with anti–CTLA-4 therapy who were colitis-free had enriched 

 and many genetic pathways involved in polyamine transport and B vitamin synthesis compared with those who developed colitis. However, an abundance of

 and other Firmicutes had a higher risk of colitis on anti–CTLA-4 therapy.

Several ongoing trials are determining how to prevent toxicity in patients with renal cancer treated with immunotherapy by using FMT to reduce or prevent posttherapeutic toxic effects.

 The gut microbiota can be altered by a defined mixture of live intestinal bacterial cultures from a healthy donor used in conjunction with immunotherapy. Similarly, FMT and drug-based metabolic modulators like metformin, nivolumab, and pembrolizumab (Keytruda) are being studied to optimize the microbiota in conjunction with immunotherapy. 

“When I first started working in this area there was hope that we would identify a simple microbe or group of microbes associated with response that could then be readily translated to a therapy of some type. However, it has become quite clear that it is not going to be quite so simple, and it is likely that signatures of response may be quite personalized,” said Lee.

In patients being treated with anti–PD-1 therapy across different cancers, the bacteria that affect drug efficacy are not the same. In one study, 

 were identified in responders, and in another study the Ruminococcaceae family was identified, and a third identified 

. It is likely that more bacteria will vary among different cancers and gut ecology.

“Understanding the disparity in taxa and identifying common functional metabolites may help determine specific aspects of the microbiome that can optimally improve ICI efficacy,” said McQuade. Newer immunotherapies may need to be designed with a microbiome-modulating therapeutic element like a probiotic supplement or metabolite to reduce variability in ICI response.

“With the complexity of the tumor microenvironment and genetic determinants involved, there will not be a single predictor of therapeutic response or toxicity. Complicated risk scores taking all these factors into

account will likely be needed to determine optimized response,” McQuade said. “Everyone who responds to therapy is not because of their microbiome, and everyone who doesn’t respond is not because of their microbiome.”

Dietary modulation to modify gut composition can potentially change the therapeutic paradigm for patients who do not respond to immunotherapy, chemotherapy, radiotherapy, or surgery.

 The ketogenic diet has shown effective management of latestage glioblastoma multiforme by arresting tumor cell growth and reducing symptoms and prevalence of edema.

The ketogenic diet has facilitated nontoxic drug delivery to tumor sites with lower dosages needed to achieve therapeutic effects. Following a ketogenic diet reshapes gut composition.

The microbiome is complex and has potential to predict response to cancer therapy and be manipulated to affect the tumor microenvironment. Current research has focused on identifying microbes involved in cancer therapy. “Given the complex interactions of the gut with immune and cancer cells, the challenge will be to find an ideal combination of bacteria and metabolites to affect the tumor microenvironment, and how to ideally introduce this combination for cancer treatment and maintenance,” Lee said. The modulation of gut microbiota will represent a novel and important adjunct to current anticancer therapeutic modalities.

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Articles

The normal gut microbiota metabolizes nutrients and drugs, maintains the gut mucosal barrier integrity, protects against pathogens, and trains and develops the immune system. The gut microbiome has been implicated in many human pathologies.

Exploring the Role of Gut Microbiome in Cancer Therapy

VISTA, or V-domain immunoglobulin suppressor of T-cell activation, is an immunoregulatory molecule involved in maintaining T-cell and myeloid quiescence.

This review describes the role of VISTA as a promising target in cancer immunotherapy.

Within the tumor microenvironment (TME), immune cells are often downregulated by activated inhibitory pathways. The resulting suppressed immune response can facilitate cancer progression. Research has identifi ed key immune checkpoint molecules, such as PD-1 and CTLA-4, that play a role in regulating these pathways.

One of the recently identified inhibitory checkpoint molecules is VISTA.

 Blocking VISTA can result in immune cells proliferating in the TME, which can help prevent cancer from progressing.

Randolph J. Noelle, PhD, professor of microbiology and immunology at the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire, provided his insights on the potential of the VISTA checkpoint molecule in an interview with 

 Noelle and his laboratory first characterized and functionally defined VISTA over 10 years ago.

“VISTA is a negative regulatory molecule. Blocking VISTA lowers the threshold for T-cell receptor activation of resting T cells. The frequency of T cells mounting a response to neoantigens should be increased,” Noelle said. 

Other inhibitory checkpoint molecules, such as CTLA-4 and PD-1, also prevent activated T cells from achieving their effector functions. As a result, targeted therapies against CTLA-4 and PD-1 have allowed T cells to proliferate and attack cancer cells in the TME and ultimately increase survival rates of patients with cancer.

Despite this benefit, increases in survival from therapies targeting CTLA-4 and PD-1 were only seen in a fraction of patients with cancer, but this did not extend to all cancer types. A gap remains in finding specific checkpoint targets to address most cancer types. 

Many potential checkpoint targets exist in addition to VISTA, including inhibitory and stimulatory checkpoint pathways such as LAG-3, TIM-3, TIGIT, OX40, and ICOS.

 However, finding the right target is a challenge, because cancer cells of different origins and individual patients with cancer cells of similar origins may respond differently to identical targeted therapies. Immunotherapeutic intervention with VISTA is of interest to investigators. 

“VISTA is an exciting new target on its own and in combination with other checkpoint inhibitors,” Noelle said. “VISTA can control the steady state activity of the resting immune system and should allow for heightened antitumor immune response.”

Research has uncovered unique features of VISTA compared with other immune checkpoint inhibitors. Other inhibitory checkpoint regulators, such as CTLA-4 and PD-1, are expressed on T cells after T-cell activation in either the priming stage (CTLA-4, to maintain T-cell anergy) or the effector stage (PD1, to prevent T-cell exhaustion).

 However, VISTA is expressed on naïve T cells. 

“A unique feature compared [with] other costimulatory molecules is that [VISTA] is constitutively expressed by the immune system,” Noelle said. VISTA is found on resting T cells and on nonactivated macrophages, Noelle added.

 Its function is to keep the immune system quiet. All other immune checkpoint inhibitors regulate the process after T cells are activated. “This gives us an opportunity to raise awareness of the resting immune system to mount immune responses to cancer,” he said. 

VISTA serves as the earliest checkpoint regulator of peripheral T-cell tolerance. It is involved in enforcing quiescence in naïve T lymphocytes when exposed to self-antigens.

Therefore, when the VISTA gene is deleted in mice, naive T cells are shown to have stronger responses to cytokine stimulation with greater expansion when exposed to antigens. 

VISTA has an extracellular domain with homology to PD-L1, a B7 family ligand.

Acting as a ligand, a VISTA-Ig fusion protein has been shown to inhibit mouse and human CD4-positive and CD8-positive T cells, as well as to reduce T-cell cytokine production such as IL-2, IL-10, TNF-α, and IFN-γ. 

 Additionally in mouse models, T cells without VISTA proliferated more than T cells with VISTA when pulsed with antigen-presenting cells.

Furthermore, VISTA is expressed on many different cells in the TME, giving it broader potential as a target than CTLA-4 and PD-1, which are relegated to activated T cells.

 For example, VISTA is expressed on myeloid-derived suppressor cells, including microglia and neutrophils, tumor-associated macrophages, and dendritic cells that all have suppressive function in the TME. 

An additional quality of VISTA exhibiting its potential in advanced cancer therapy is that its upregulation in various cancer types increases as cancer worsens by grade or stage.

 Studies have shown that VISTA gene expression was upregulated to a greater extent in higher-grade gliomas than in lower-grade gliomas, and upregulation was associated with worse patient outcomes. Similarly, VISTA has been found to be upregulated in higher grades of oral squamous cell carcinomas, gastrointestinal cancers, and prostate cancers compared with lower grades of the diseases. 

VISTA may also have benefit in relation to other checkpoint inhibitors, as specific cancers do not respond well to anti–PD-1 or anti–CTLA-4 therapies but may respond to anti-VISTA approaches. 

For example, pancreatic cancer does not respond well to anti–PD-1 or anti–CTLA-4 therapy. However, VISTA-Ig fusion protein inhibits the cytokine production of CD8-positive T cells in the pancreatic TME.

Lastly, specific cancers may also develop resistance to anti–CTLA-4 or anti–PD-1 therapies. Interestingly, some cancers have been shown to upregulate VISTA in these situations. In patients with melanoma treated with anti–PD-1 therapies, VISTA was upregulated.

 In prostate cancer, after ipilimumab (Yervoy) therapy, VISTA inhibitory molecules increased in macrophages in the TME. 

Therefore, VISTA upregulation may be a key mechanism by which cancers develop resistance to other immunotherapies.

As a result of this finding, anti-VISTA therapies have potential for use as combination therapy with anti–CTLA-4 and anti–PD-1 therapies in a nonoverlapping fashion. 

Several other cancers have been shown to have high VISTA expression with worse overall survival (OS), making VISTA a potential therapeutic target. Brcic et al found high numbers of regulatory T cells with VISTA expression in squamous cell and adenocarcinomas of the lung.

 VISTA was expressed at higher levels in microsatellite unstable colorectal cancers compared with microsatellite stable tumors.

 Xie et al showed that high VISTA expression was associated with worse OS in patients with colorectal cancer.

Likewise, high VISTA expression has been reported in ovarian and endometrial cancers, and VISTA messenger RNA expression was positively correlated with immune escape– modulating genes.

Furthermore, in mice with ovarian cancer, an anti-VISTA antibody prolonged the survival of tumor-bearing mice.

Several VISTA-targeting inhibitors are in development and have undergone phase 1 and 2 trials. 

An oral agent, CA-170, targeting both VISTA and PD-L1 in a phase 2 trial showed a clinical benefi t rate of 75% and progression-free survival of 19.5 weeks in patients with nonsquamous non–small cell lung cancer (NSCLC).

Furthermore, a phase 2 trial (NCT03201458) of patients with biliary tract cancer receiving atezolizumab (Tecentriq) with MEK inhibitor cobimetinib (Cotellic) showed that patients with higher baseline or changes in VISTA expression on circulating T cells had longer progression-free survival than those without high VISTA expression.

Several molecules targeting VISTA are undergoing phase 1 trials. HMBD-002 is an IgG4 antibody targeting VISTA and was shown to increase infl ammatory cytokines and inhibit tumor growth in animal models.

 The therapy is in clinical trials for either monotherapy or in combination with PD-1 inhibitors for treatment of patients with triple-negative breast cancer and NSCLC. 

Additionally, a phase 1 trial (NCT04475523) is ongoing to find the recommended phase 2 dose of an anti-VISTA molecule, CI-8993, in patients with relapsed or refractory solid tumors. Another agent, W0180, is an anti-VISTA antibody being explored in a phase 1 trial (NCT04564417) as monotherapy or in combination with pembrolizumab (Keytruda) to determine dosing and schedule of administration.

Despite the potential across multiple cancer types, VISTA remains variable in expression based on the tissue, restricting the therapeutic potential of its inhibition. Although VISTA is expressed in higher levels in cholangiocarcinoma, glioblastoma multiforme, clear cell renal cell carcinoma, acute myeloid leukemia, and pancreatic adenocarcinoma, it is also expressed in low levels in many other cancer types.

Describing the role of VISTA, an immunoregulatory molecule involved in maintaining T-cell and myeloid quiescence, as a promising target in cancer immunotherapy.

Abdullah Hashmi, MD | Authors

Articles

Exploring the Role of Gut Microbiome in Cancer Therapy

VISTA Emerges as a Promising Immunotherapy Target in Cancer