2020-05-08| R&DTechnology

AACR 2020: Modifications in Tumor Microenvironment and Host Microbiome, a Potential Therapeutic Strategy for Immunotherapy

by Tulip Chakraborty
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By T. Chakraborty, Ph.D.

Chemotherapy and targeted therapies have dominated the cancer therapeutics space for a long time. However, cancer cells have also developed strategies to elude such procedures, forcing scientists to look for other avenues.

Lately, immunotherapeutic approaches like immune checkpoint protein inhibitors and Chimeric antigen receptor T-cells have come to the fore where the host’s immune system is used against cancer [1]. The recent developments in the field of the gut microbiome and personalized medicine are being touted as potential cofactors for these immunotherapies. This was one of the topics discussed in this year’s virtual AACR meeting.


Berry, a Potential Adjuvant for Immune Checkpoint Inhibitor Therapy?

Cancer cells have been shown to evade the host immune system by upregulating the immune checkpoint proteins, thereby lowering the immune response of the body. Hence, immune checkpoint inhibitors are widely used as cancer therapies.

Studies have shown that microbes such as Akkermansia muciniphila and Ruminococcus are present in abundance in the gut microbiome of patients who respond to immune checkpoint inhibition. This suggests probable crosstalk between the host gut microbiome and immune response. A polyphenol rich berry called Myrciaria dubia has recently been shown to improve the gut microbiome as well as modulate inflammation.

Dr. Bertrand Routy’s team from the University of Montreal tested the hypothesis that this berry induces the gut microbiome to improve the efficacy of the anti-PD-1 immune checkpoint inhibitor in a mouse model. The berry extract was administered orally to both PD-1 sensitive and resistant mice, followed by anti-PD-1 antibody treatment. 16S sequencing and flow cytometry were performed to understand the microbiome changes and modifications in the host immune response.

The group reported that the oral administration of Myrciaria dubia significantly improved the efficacy of anti-PD-1 therapy in both mice. Further, 16S sequencing showed that the berry extract improved the diversity of the gut microbiome, increased the number of cytotoxic T cells, which in turn improved the overall immune response.

Moreover, it also enhanced the presence of A. muciniphila and Ruminococcus, which have been linked to increased efficacy of PD-1 therapy. Additionally, the group also isolated the bioactive component of the berry, which had antitumor activity. In conclusion, the presenting author Dr. Messaoudene suggested that supplementation of the bioactive compound along with the gut bacteria Ruminococcus may work as combination therapy along with anti-PD-1 therapy [2].


Re-modeling the Tissue Microenvironment Potentiates the Efficacy of Immunotherapy

The tumor microenvironment plays an extremely important role in cancer progression. It is made up of vasculatures, a heterogeneous population of cancer cells, infiltrating and resident host cells, other secreted factors, and extracellular matrices. Cancer cells use the tumor microenvironment to bypass the effect of drugs as well as develop resistance against various therapies.

The modification of the tumor microenvironment to ease the path for immune cells to interact with the cancers is an active area of research. The role of tumor matrices in generating an “inflamed microenvironment” suitable for immunotherapy is not well understood yet.

Dr. Fotis Asimakopoulos’s group at the University of California, San Diego, is researching the role of versican (VCAN), chondroitin sulphate matrix, in regulating the tumor microenvironment and its effect on immunotherapy. The proteolytic cleavage of VCAN releases the bioactive fragment versikine, which has been shown to trigger IRF-8 dependent myeloid cell infiltration and Baft3 dependent maturation and mobilization of dendritic cells in vitro.

Breast cancer cells and versikine expressing cells were implanted in mice, and once the tumors were 1000 mm³ in volume, they were harvested, and flow cytometry was performed to understand the immune cell profile of the tumor microenvironment. Results suggest that versikine expressing tumors were enriched in dendritic cells, while there were no significant changes in tumor infiltrating monocytes.

Stimulator of interferon genes (STING) agonist therapy has been recently used to induce immune cells to produce cytotoxic factors like interleukins and interferons to kill cancers. When versikine was injected intratumorally along with STING agonists to determine its effectiveness as a co-treatment, it was found to significantly reduce tumor growth.

Furthermore, increased cytotoxic T cells and necrosis were observed in tumor cells suggesting that modifying the tumor matrix may play an important role in immunotherapy. The authors concluded that versikine could be potentially used as a co-therapy for immunotherapies like STING agonist therapies to facilitate the path for immune cells to access the tumor microenvironment.


Gut Microbiome, a Probable Biomarker of Toxicity for Immune Checkpoint Inhibition Therapy

The development of immune checkpoint inhibitors has revolutionized the field of cancer therapy. Yet, challenges like resistance or toxicity from immune related adverse events lead to the failure of treatment completion. The host microbiome has been shown to modulate physiological inflammation as well as immune related adverse events suggesting an interrelationship with immune checkpoint inhibition.

Dr. Long and colleagues from the University of Sydney, performed sequencing to analyze the fecal microbiome load on 38 stage III melanoma patients treated with immune checkpoint inhibitors anti-PD1 and anti-CTLA4 antibodies in the neoadjuvant setting. Further, the immune cell population was analyzed using mass cytometry, and machine learning was employed to understand the ability of the microbial population to predict immune checkpoint inhibition therapy response.

The study found that 6 of the patients who did not respond to the therapy, and 11 of the patients who developed adverse immune response had lower gut microbiome diversity before the start of treatment. Patients who possessed lower bacterial diversity had an enhanced number of effector and memory CD4 and CD8 T cells in the blood and increased numbers of circulating natural killer cells.

Finally, the patients who responded to the therapy had increased load of Ruminococcaceae and methanogenic archaea in their gut, and both of these bacteria have been linked to improved immune checkpoint inhibitor therapy efficacy. Further, these patients also had an abundance of butyrate which correlated to the response against adverse immune response. The study concluded that diversity in the microbiome could be used to predict the development of adverse immune response in patients treated with immune checkpoint inhibitors [4].

Related Article: AACR 2020: What Does Cancer Therapy Mean in the Time of COVID-19?



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