in a mouse model of pancreatic cancer. This resulted in stimulation of the immune response, which suppressed tumor growth.
published in Cell
, was led by Dr. Florencia
McAllister, MD, who holds joint appointments as Assistant Professor in the
Department of Clinical Cancer Prevention and Department of Gastrointestinal
Medical Oncology at the University of Texas MD Anderson Cancer Center, Houston,
What are the Problems Associated with Pancreatic
The most common type of pancreatic cancer
. This type of pancreatic cancer has problems both
when it is diagnosed at a late-stage or at an early-stage. On the one hand,
when the cancer is diagnosed at a late-stage, only 9 percent of patients
survive till five years. On the other hand, when the cancer is detected at an early stage and
surgically treated, there is a high recurrence rate, as a result of which the
median duration of survival of the patients is only 24-30 months. Moreover, no
genomic markers have been identified that can explain the reason for the
long-term survival of some of the patients.
What is the Role of Tumor Microbiome on
Pancreatic Cancer Survival?Gut microbiome plays an important role in modulation of cancer immunotherapy.
However, it is not known
whether the bacterial flora present on tumors - the tumor microbiome - also plays a role in cancer.
To answer this
question, the research team analyzed the DNA
(deoxyribonucleic acid) of bacteria present on tumors from long-term pancreatic cancer survivors
it with that from short-term survivors. The study included two independent
cohorts - one from MD Anderson Cancer Center and the other from Johns Hopkins
In the MD Anderson
cohort, the median long-term survival was 10 years (22 patients) and the median
short-term survival was 1.6 years (21 patients). In the case of the Johns
Hopkins cohort used for validation purposes, 15 patients survived longer than
10 years, while 10 survived less than five years.
Sequencing the 16S
rRNA (ribosomal ribonucleic acid) gene, clearly showed that the long-term
pancreatic cancer survivors had a greater bacterial diversity on the surface of
the tumors, compared to short-term survivors. Based on the bacterial diversity,
it was found that a high bacterial diversity was linked to longer survival
(median survival of 9.66 years), while low bacterial diversity was linked to
shorter survival (median survival of 1.66 years).
based on bacterial diversity, were independent of other factors such as prior
cancer therapy, exposure to antibiotics, and body mass index (BMI). This makes
bacterial diversity a good predictor of survival in the case of patients
undergoing pancreatic cancer surgery. Moreover, it also acts as an excellent
biomarker for monitoring the progression of pancreatic cancer.
finding was that the preponderance of particular bacterial species on the
tumors was associated with the duration of survival. For example, long-term survivors
had larger numbers of bacteria belonging to the genus Pseudoxanthomonas
, and Streptomyces
, as well as the bacterium Bacillus clausii
. Presence of these
species of bacteria predicted a better outcome for patients in both the MD Anderson
and Johns Hopkins cohorts.
What is the Link between Tumor Microbiome and
the Immune System?
Tumor microbiome is associated with immunity. Immunohistochemical techniques
revealed that in
the tumors of long-term pancreatic cancer survivors of both the MD Anderson and
Johns Hopkins cohorts, there were greater numbers of T-cells, particularly CD8+ T-cells
, which are
responsible for cell-mediated immunity. These observations corroborated with
previous studies which found that long-term survivors exhibited more vigorous
The research team also found that immune cell infiltration was
strongly correlated with bacterial diversity of the tumors. Moreover, immune
cell infiltration and T-cell activation were strongly linked to the abundance
of the three types of bacteria detected on the surface of tumors of long-term
pancreatic cancer survivors.
of this link between the tumor microbiome and the immune system encouraged the
researchers to look for a way to alter the tumor microbiome.
Can Tumor Microbiome be Altered by Gut Microbiome?
microbiome cannot be altered directly. However, it was hypothesized that the
gut microbiome could possibly alter the tumor microbiome, if there was a cross-talk
between the two microbiomes.
Bacteria in the
gut, in the tumors and in adjacent tissues were compared in 3 patients
undergoing surgery. It was found that the gut microbiome represented 25 percent
of the tumor microbiome. However, these gut bacteria were absent in the normal,
adjacent tissues. This indicated that there was indeed a link between the gut
microbiome and tumor microbiome and that the gut bacteria were capable of
colonizing pancreatic tumors.
transplantation (FMT) from patients with advanced pancreatic cancer into mice
revealed that the gut microbiome from the patients represented around 5 percent
of the resultant tumor microbiome in mice. Moreover, FMT altered 70 percent of
the total tumor microbiome. This finding proved that FMT was capable of completely altering the bacterial population of the tumor microbiome.
Is Fecal Microbiota Transplantation (FMT)
Dependent on the Immune System?
FMT was performed
in mice from patients with advanced pancreatic cancer, long-term survivors, and
healthy controls. Five weeks after the fecal transplantation, it was observed
that the mice which received FMT from advanced cancer patients had much larger
tumors than those which received FMT from long-term survivors (70% smaller
tumor size) or healthy controls (50% smaller tumor size).
studies revealed that the mice which received FMT from long-term survivors had
higher levels of activated CD8+
T-cells compared to the other two groups. The mice
that received FMT from patients with advanced pancreatic cancer had higher
levels of regulatory T-cells (Tregs) and myeloid-derived suppressor cells
(MDSC), both of which are capable of suppressing the immune response.
In order to
evaluate whether the effect of FMT was dependent on the immune system, T-cells
were depleted in mice that received fecal transplants from long-term survivors.
This led to complete blocking of anti-tumor activity of the fecal transplants.
This clearly showed that the effect of FMT is dependent on the immune system.
concluded:"Results of the FMT experiments
represent a significant therapeutic opportunity to improve pancreatic cancer treatment by altering the tumor immune microenvironment."
added: "There is promise here but we have
a lot of work ahead."
The research was
funded by multiple organizations, foundations, institutes, and award grants.
Some of these include the American Gastroenterological Association Research Foundation,
MD Anderson's Moon Shots ProgramTM
, MD Anderson Cancer Center,
Stanford University-Emerson Collective Cancer Research Fund, Stand Up To Cancer
- Lustgarten Foundation, the National Cancer Institute of the National
Institutes of Health, the Pancreatic Cancer Action Network-AACR Career
Development Award, and the Paul Calabresi Career Development
Award for Clinical Oncology (PCACO) K12.Reference :
- Pancreatic cancer - (https://www.mdanderson.org/newsroom/bacteria-on-tumors-influences-immune-response-and-survival-of-pa.h00-159305412.html)