Can Viruses Help Treat Cancer?

Summary

New research published in Nature suggests that genetic remnants from ancient viral infections, known as endogenous retroviruses (ERVs), influence the effectiveness of immunotherapy in lung cancer patients. Antibodies targeting ERV-encoded proteins may enhance the immune response to cancer, with 45% of patients showing a positive reaction to immunotherapy. This discovery could pave the way for developing vaccines that boost antibody production at tumor sites, potentially improving immunotherapy outcomes. Additionally, oncolytic viruses are being explored as a novel class of cancer therapy, with the potential to directly kill tumor cells or stimulate antitumor immunity.

Takeaways

• 🧬 Genetic elements from ancient viral infections may influence the response to immunotherapy in cancer patients.
• 💉 Immunotherapy, particularly immune checkpoint blockade (ICB), uses the body's immune system to fight cancer by inhibiting checkpoint proteins like PD-1 and PD-L1.
• 🔍 ICB is not universally effective, with about 70% of lung cancer patients not responding to the therapy, and the reasons behind this are not fully understood.
• 🦠 B cells and the antibodies they produce are implicated in the response to ICB, with B cell expansion around tumors potentially predicting a positive response to checkpoint inhibition.
• 🐁 In a mouse model of lung adenocarcinoma, ICB treatment promoted survival and increased anti-tumor antibodies, some of which target endogenous retroviruses (ERVs).
• 🌐 ERVs are remnants of retroviruses that infected our ancestors and are now part of the human genome, with over 8% of it composed of retroviral sequences.
• 🛡️ ERVs do not typically encode infectious viral particles but can produce viral-like proteins, and they are upregulated in cancer tissues, making them targets for antibodies.
• 🏥 Research suggests that anti-ERV antibodies are key in anti-tumor immunity and may enhance the effectiveness of ICB treatment in lung cancer.
• 🧬 The study indicates that ERVs could 'trick' the immune system into recognizing tumor cells as infected, thus activating an immune response to eliminate them.
• 🧬 Human patient samples showed a correlation between the presence of anti-ERV antibodies and a positive response to ICB, as well as better overall survival rates.
• 🛑 Oncolytic viruses (OVs) are a new class of cancer therapy that can kill tumor cells or induce antitumor immunity, and their use is being explored for more effective delivery methods.
• 🧬 The concept of using cells as carriers for the delivery of OVs by integrating viral genetic material into the human genome is a promising area of research.

Q & A

Why do some cancer patients respond to immunotherapy while others do not?

The script suggests that genetic elements from ancient viral infections, known as endogenous retroviruses (ERVs), may influence the response to immunotherapy. Antibodies targeting proteins encoded by these sequences could enhance the effectiveness of immunotherapy in lung cancer patients.

What is immune checkpoint blockade (ICB) and how does it work?

ICB is a cancer treatment method that leverages the body's immune system to fight cancer. It works by inhibiting interactions between checkpoint proteins, such as PD-1 and PD-L1, on T cells and other cells. This prevents the 'off' signal from being sent to T cells, allowing them to remain active and destroy tumor cells.

What is the problem with the effectiveness of ICB treatment?

Approximately 70% of lung cancer patients do not respond to ICB treatment. The exact reasons for this are not fully understood, but the script suggests that B cells and the antibodies they produce may be related to the response to ICB.

What role do B cells play in the response to checkpoint blockade?

B cell expansion in tissue around tumors can be used to predict whether a tumor will respond positively to checkpoint inhibition. The antibodies produced by B cells, particularly those targeting antigens expressed by tumors, can flag cancer cells for destruction by immune cells.

What are endogenous retroviruses (ERVs) and why are they significant in this study?

ERVs are DNA remnants of retroviruses that infected our ancestors thousands or millions of years ago. They are significant because the study found that antibodies targeting ERV glycoproteins are key players in anti-tumor immunity and responses to ICB treatment.

How does the expression of ERVs in cancer tissues relate to the immune response?

ERVs are generally upregulated in cancer tissues compared to healthy cells. The study suggests that the expression of ERV glycoproteins in mouse cancer cells and the presence of anti-ERV antibodies can help prolong survival and contribute to the success of ICB treatment.

What is the potential application of ERVs in cancer treatment according to the study's findings?

The study suggests that developing cancer treatment vaccines comprised of ERV genes could boost antibody production at a patient's cancer site, potentially improving immunotherapy outcomes.

What are oncolytic viruses (OVs) and how do they contribute to cancer therapy?

Oncolytic viruses are a new class of cancer therapy that can directly kill or lyse tumor cells or induce antitumor immunity. They are engineered to enhance immune stimulation and/or remove pathogenicity-associated genes.

What challenges are associated with the administration of oncolytic virus therapeutics?

Challenges include inefficient targeting of tumor sites, the risk of cytokine storm, and the difficulty of administering OVs via the most desirable route, intravenous delivery, to reach both primary and metastasized tumors.

What is the novel approach proposed by researchers in the Journal of Virology to address the challenges of OV administration?

Researchers propose using cells as carriers for the systematic delivery of OVs by integrating cDNA from an oncolytic coxsackievirus into the genome of human cells, allowing for the production and release of viral particles potentially at the tumor site.

What do the findings of the study and the report in the Journal of Virology suggest about the role of viruses in cancer immunity and therapeutics?

The findings suggest that viruses and their integrated genetic material play a significant role in cancer immunity and therapeutics, both through the immune response triggered by ERVs and the direct action of oncolytic viruses in killing tumor cells and modulating immune responses.

Outlines

00:00

🧬 Role of Ancient Viruses in Cancer Immunotherapy

The first paragraph delves into the enigma of varying responses to immunotherapy among cancer patients, particularly lung cancer, which is the leading cause of cancer-related deaths globally. The focus is on immune checkpoint blockade (ICB), a method that harnesses the body's immune system to combat cancer by inhibiting checkpoint proteins, such as PD-1 and PD-L1, which are exploited by cancer cells to evade immune destruction. Despite advancements, ICB's effectiveness is inconsistent, with approximately 70% of lung cancer patients not responding to the therapy. The research suggests that B cells and the antibodies they produce may play a critical role, with B cell expansion around tumors potentially predicting a positive response to ICB. The study investigates the immunological basis of this response using a mouse model and discovers that antibodies targeting endogenous retroviruses (ERVs), genetic remnants from ancient viral infections, are a dominant target in lung cancer and may enhance the effectiveness of ICB. ERVs, which make up over 8% of the human genome, are upregulated in cancer tissues and produce transcripts that can encode parts of a virus, influencing gene regulation and immune responses. The findings indicate that anti-ERV antibodies are crucial in anti-tumor immunity and could be key to improving immunotherapy outcomes.

05:03

🛡️ Harnessing Viral Genetics for Cancer Therapy

The second paragraph expands on the role of viruses in cancer therapy, highlighting the potential of using viral genetic material to enhance anti-tumor immunity and the success of ICB treatment. It discusses the possibility of developing vaccines containing ERV genes to boost antibody production at the tumor site, thereby improving immunotherapy outcomes. The paragraph also introduces oncolytic viruses (OVs), a novel class of cancer therapy that includes a variety of viruses engineered to stimulate the immune system and/or remove pathogenicity-associated genes. OVs can be challenging to administer, with intratumoral administration being common but intravenous delivery being more desirable for reaching primary and metastatic tumors. The paragraph describes a study that proposes a solution to these challenges by integrating cDNA from an oncolytic coxsackievirus into human cells, allowing for the production and release of viral particles at the tumor site. This approach could be a viable method for the systematic delivery of OV therapy, although further research is needed to optimize the system for in vivo applications. The summary underscores the importance of viruses and their integrated genetic material in cancer immunity and therapeutics, suggesting a promising direction for future cancer treatments.

Keywords

💡Immunotherapy

Immunotherapy is a type of cancer treatment that helps the body's immune system fight cancer. In the script, it is highlighted as a method that exploits the immune system to combat cancer, particularly through immune checkpoint blockade (ICB). The theme of the video revolves around understanding why some patients respond to immunotherapy while others do not, with a focus on the role of antibodies and genetic elements.

💡Genetic Elements

Genetic elements refer to the parts of DNA that have specific functions, such as encoding proteins or regulating gene expression. In the context of the video, 'genetic elements leftover from ancient viral infections' are discussed as they may influence the response to immunotherapy. These elements, particularly endogenous retroviruses (ERVs), are shown to have a significant impact on the body's immune response to cancer.

💡Antibodies

Antibodies are proteins produced by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The script discusses how antibodies targeting proteins encoded by ERV sequences may enhance the response of lung cancer patients to immunotherapy, indicating a direct link between these immune proteins and the effectiveness of cancer treatment.

💡Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. The video script emphasizes the significance of lung cancer as the primary focus of the study being discussed, highlighting the importance of finding effective treatments for this prevalent disease.

💡Immune Checkpoint Blockade (ICB)

ICB is a cancer treatment method that works by inhibiting interactions between checkpoint proteins on immune cells and other cells, allowing the immune system to remain active and destroy tumor cells. The script explains how ICB is not always effective, and the research aims to understand why, focusing on the role of B cells and antibodies.

💡B Cells

B cells are a type of white blood cell that produces antibodies. The script suggests that B cell expansion in tissue around tumors could predict a positive response to checkpoint inhibition, indicating a crucial role for B cells in the body's immune response to cancer.

💡Endogenous Retroviruses (ERVs)

ERVs are remnants of ancient retroviruses that infected our ancestors and became part of the human genome. The script explains that ERVs are upregulated in cancer tissues and that antibodies targeting ERV glycoproteins are linked to a positive response to ICB treatment, illustrating the connection between these genetic relics and the body's fight against cancer.

💡Anti-ERV Antibodies

Anti-ERV antibodies are antibodies that target the proteins associated with ERVs. The script discusses how these antibodies help prolong the survival of animals treated with ICB, suggesting that they play a key role in anti-tumor immunity and the success of immunotherapy.

💡Oncolytic Viruses (OVs)

OVs are viruses that are engineered to specifically infect and kill cancer cells. The script mentions OVs as a new class of cancer therapy that can also induce antitumor immunity, similar to the role of ERVs and their antibodies.

💡RNA Virus

An RNA virus is a virus that has RNA as its genetic material. The script discusses a study where cDNA from an oncolytic coxsackievirus, an RNA virus, is integrated into the genome of human cells to potentially produce and release viral particles at the site of a tumor, indicating a novel approach to cancer therapy.

💡Cancer Immunity

Cancer immunity refers to the body's immune response to cancer. The script highlights the importance of understanding and leveraging the immune system's ability to recognize and fight cancer, particularly through the use of immunotherapy and the targeting of ERVs and OVs.

Highlights

New research in Nature suggests that genetic elements from ancient viral infections may influence the response to immunotherapy in cancer patients.

Antibodies targeting proteins encoded by these ancient viral sequences may enhance the effectiveness of immunotherapy for lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, with advancements in immune checkpoint blockade (ICB) therapy showing promise.

ICB therapy works by inhibiting checkpoint proteins, allowing T cells to remain active and destroy tumor cells.

Approximately 70% of lung cancer patients do not respond to ICB therapy, and the reasons are not fully understood.

B cells and the antibodies they produce are implicated in the response to checkpoint inhibition, with B cell expansion areas potentially predicting positive responses.

Mice with lung cancer treated with ICB showed increased survival rates and higher levels of anti-tumor antibodies.

Endogenous retroviruses (ERVs) are ancient viral DNA integrated into the human genome and are linked to the immune response and gene regulation.

ERV glycoproteins are highly expressed in mouse cancer cells, and antibodies against them help prolong survival in ICB-treated mice.

ERVs trick the immune system into treating tumor cells as infected, acting as an 'alarm system' for immune response.

Human lung cancer patients with antibodies against a human ERV glycoprotein responded positively to ICB therapy.

ERV expression levels and anti-ERV antibodies are correlated with better patient survival rates in lung cancer.

The study advances understanding of the link between humoral immune responses, cancer, and immunotherapy, suggesting potential for B cell expansion methods.

Future research could develop vaccines using ERV genes to improve immunotherapy outcomes by boosting antibody production at the cancer site.

Oncolytic viruses (OVs) are a new class of cancer therapy that can kill tumor cells or induce antitumor immunity.

Challenges with OV therapeutics include inefficient tumor targeting and the risk of cytokine storm, necessitating new delivery methods.

A novel approach proposes using cells as carriers for OVs by integrating viral cDNA into the human genome for targeted virus production.

The concept of using cells to deliver OVs needs further optimization and in vivo testing for practical cancer treatment applications.

Viruses and their integrated genetic material are emerging as important factors in cancer immunity and therapeutics.

Transcripts

Why do some cancer patients respond to  immunotherapy, while others don’t? New research  

in Nature suggests that genetic elements leftover  from ancient viral infections may play a role,  

demonstrating that antibodies targeting  the proteins encoded by these sequences  

may boost lung cancer patients’  response to immunotherapy. Today,  

we will discuss these results and what  they mean for cancer treatments. We  

will also explore the broader, deliberate  application of viruses for treating cancer. 

Welcome to Microbial Minutes, the American  Society for Microbiology’s update on what’s  

hot in the microbial sciences. I’m Madeline  Barron, Science Communication Specialist at ASM.

The study we are discussing today focuses on  lung cancer, the leading cause of cancer-related  

deaths worldwide. There have been notable  advancements in cancer therapeutics in  

recent years, particularly in the context  of immune checkpoint blockade, or ICB. 

This treatment method exploits the  body’s immune system to fight cancer.  

It involves inhibiting interactions between  “checkpoint proteins,” such as PD-1 and PD-L1,  

on T cells and other cells (i.e., normal or  cancer cells), respectively. These interactions  

turn off the T cells and prevent them from  destroying their binding partners. Cancer  

cells can exploit this system by upregulating  checkpoint proteins to evade immune destruction. 

Blocking these protein-protein interactions  prevents the “off” signal from being sent,  

and allows T cells to remain active  and, ultimately, to destroy tumor cells. 

The problem is that ICB is not always  effective. In fact, roughly 70% of  

patients with lung cancer fail to respond to the  therapy, though why this is unclear. However,  

B cells—particularly the antibodies they  produce—may have something to do with  

it. Indeed, research suggests that areas of B cell  expansion in tissue around tumors can be used to  

predict whether a tumor will respond positively  to checkpoint inhibition. The researchers here  

wanted to better understand these immunological  underpinnings of the checkpoint blockade response.

Using a mouse model of lung adenocarcinoma, the  scientists tested the effect of ICB (specifically  

anti-PD-L1 therapy) on mice with cancer. They  found that ICB treatment promoted survival of  

the mice. Moreover, compared to control  animals, those treated with ICB exhibited  

increased titers of anti-tumor antibodies. These antibodies bind antigens expressed  

by tumors and, in doing so, flag cancer cells  for destruction by immune cells. In this study,  

the scientists discovered that a dominant  target of antibodies in mice with lung  

cancer are surface proteins associated  with endogenous retroviruses, or ERVs.

But what exactly are ERVs? Well, retroviruses,  such as HIV, are viruses whose RNA genome is  

reverse transcribed to produce DNA  when they infect a host. The DNA is  

then integrated into the host cell’s genome. ERVs are DNA “relics” of retroviruses that  

infected our ancestors thousands, or even  millions, of years ago. The DNA from these  

ancient retroviruses became stable elements  of the genome, passed from generation to  

generation. In fact, over 8% of the human genome  is composed of sequences of retroviral origin. 

Because the sequences have been modified  by host processes and mutated over time,  

ERVs don’t generally encode for infectious viral  particles. They do, however, produce transcripts  

that can encode parts of a virus (for example,  envelope proteins). ERVS play an important role  

in the regulation and expression of genes,  including those involved in immune responses. 

Furthermore, in cancer tissues, ERVs are  generally upregulated compared to healthy cells. 

With that in mind, the researchers here found  that ERV glycoproteins were highly expressed  

in mouse cancer cells. Moreover, anti-ERV  antibodies helped prolong survival of animals  

treated with ICB. The findings implicate anti-ERV  antibodies as key players in anti-tumor immunity  

and immunotherapy responses. Dr. George Kassiotis,  the senior author on the study, noted in a recent  

BBC News article that, essentially, ERVs “trick  the immune system into believing that the tumour  

cells are infected and it tries to eliminate  the virus,” acting as a sort of “alarm system.”

Investigations using samples from human  patients with lung cancer from multiple  

cohorts revealed similar results. The  scientists found that plasma from 45% of  

patients with lung adenocarcinoma tested (out  of 80 patients total) had antibodies reactive  

against a glycoprotein from a human ERV. As was  observed in mice, when the scientists tested  

titers of these antibodies in 7 patients  with lung adenocarcinoma receiving ICB,  

they found that treatment boosted anti-ERV  antibodies in all of the patients. 

Furthermore, when the researchers examined  RNA-seq data from a separate cohort of patients,  

they found that expression levels of another  human ERV were higher in patients with lung  

adenocarcinoma who response to ICB compared to  those that did not. The expression levels also  

correlated with overall patient survival. Though these data are correlative,  

collectively the findings point  to involvement of ERV expression,  

and ERV envelope-targeting antibodies, in  anti-tumor immunity and successful ICB treatment.

These results are important for several reasons.  For one, they advance understanding on the links  

between humoral immune responses (specifically  anti-tumor antibodies), cancer and immunotherapy,  

which the authors note could be used to inform  methods for targeting expansion of B cells  

to predict response of, or sensitize,  tumors to immune checkpoint blockade. 

Moreover, in a recent article in the Guardian,  Dr. Kassiotis noted that additional research  

could lead to strategies for developing  cancer treatment vaccines comprised of  

ERV genes to boost antibody production  at a patient’s cancer site and, ideally,  

improve immunotherapy outcomes.  Essentially, we may be able to  

therapeutically capitalize on the genetic  relics of our ancestor’s viral infections.

Now, this study illustrated an example whereby  viral infection—specifically integration of  

viral DNA into the host genome—indirectly  helps combat cancer. However, viruses are  

also deliberately deployed to defeat tumor cells. These viruses, called oncolytic viruses, or OVs,  

represent a new class of cancer therapy.  They come in a variety of different types,  

from adenoviruses to herpes viruses, and defeat  cancer by directly killing or lysing tumor cells,  

or inducing antitumor immunity, similar to  what was outlined in the previous paper. 

OVs are generally engineered to boost immune  stimulation and/or remove pathogenicity-associated  

genes. However, administration of OV therapeutics  can be challenging. Most are administered  

intratumorally, though intravenous delivery  is most desirable given its potential for  

reaching primary and metastasized tumors. Still,  issues like inefficient targeting of tumor sites,  

risk of cytokine storm, and more make  this route of administration difficult.

In a new report in Journal of Virology,  researchers propose a solution that draws  

some loose parallels with the study we just  discussed. That is, the scientists explored  

whether cDNA from an oncolytic coxsackievirus—an  RNA virus, but not a retrovirus—could be  

deliberately integrated into genome of human  cells. The idea is that expression of the  

cDNA leads to production and release of viral  particles, potentially at the site of a tumor.

To do this, the researchers integrated cDNA  from the coxsackievirus in a human kidney  

cell line and passaged the cells multiple times.  They found that viral cDNA expression remained  

stable after passage, and the cells continued  to release viral particles into the surrounding  

media. Moreover, there were no changes in the  morphology, growth rate or virus generation  

ability of the cells over time. The findings support the concept  

that cells can be used as carriers for the  systematic delivery of OVs. To that end,  

more research would be needed to optimize  the system, such as fine-tuning expression  

and production of virus in specific environments  (i.e., the tumor microenvironment). In addition,  

these experiments were done entirely in vitro.  The findings have yet to be explored for in vivo  

applications for combatting cancer,  though are an intriguing first step.

So, what have we learned about viruses and  cancer immune responses and treatments? First,  

antibodies targeting ERVs play an important  role in anti-tumor immune responses and may  

contribute to immunotherapy response in the  context of lung cancer. On a broad scale,  

viruses are emerging as key players in the field  of cancer therapy. Oncolytic viruses can, and are,  

being used to kill tumor cells and modulate  immune responses. New research suggests that  

incorporating viral genetic material into cells  could be a viable delivery method for OV therapy. 

Ultimately, these findings point to  the importance of viruses--and their  

integrated genetic material--in  cancer immunity and therapeutics.

That’s all for today. Be sure to ring  the bell to be notified whenever a new  

Microbial Minutes drops. I’m  Madeline Barron. As always,  

thank you for listening, thanks to Ray Ortega  for production and I’ll see you next time.