Rock a bye baby

It is no secret that babies are born with a feeble immune system. This is what makes them so prone to all the sniffles in the first few months. In particular, babies are susceptible to Listeria monocytogenes infection.  Through colostrum and breast milk, the babies are passively infused with antibodies that help them while their own immune system develops. At the same time, the baby’s gut is colonized with gut bacteria- bacteria that are to form a synergistic relationship with the host and provide the delicate balance. 

There exists a tug-of war in the newborn baby between the developing immune system and gut bacteria colonization. The immune system develops at the fastest rate in weeks immediately following birth- coinciding with gut bacteria dissemination. Now we all know how an imbalance of gut bacteria can lead to a number of digestive disorders. So how does the body protect the gut microbes from an immune attack? A recent study in Nature details the discovery of a new subset of erythroid cells that are characterized by the presence of CD71 marker. These cells are produced predominantly in the first few weeks of life and play an important role in suppressing the immune reaction to the gut bacteria. Mice that were depleted of this cell subset were increasingly susceptible to digestive disorders and stomach infections. CD71+ cells are produced less frequently as we age, probably because they are not needed as much anymore.

What this means: It has been a matter of great surprise that our immune system conveniently lets a host of foreign microbes colonize our gut. While beneficial, it was always something that immunologists wondered about – why does the immune system not attack the gut bacteria? How does the immune system establish tolerance to them? This recent study provides some important insights into this area. The presence of the CD71+ erythroid cells early on helps establish the synergistic relationship between gut microbes and the host – a relationship that lasts a lifetime.

 

Image courtesy: Taken by Robert Broadie on 1 January 2005 (wikimedia commons)

The tumor – a (modified) immune organ?

I was scouting for articles  this week to discuss on this blog – And I came across a few interesting ones . But one article that I happened to chance upon while I was doing some research for work caught my fancy. I started this blog so I could write about all aspects of immunology and about a wide range of diseases (and encourage me to read scientific articles that were out of my research realm). So I was a little apprehensive about writing about cancer again. But this paper made me stop in my tracks and ponder longer than I have on any scientific subject in a while.  And I thought, well, I just need to write about this.

A tumor is viewed as a unwelcome addition to our body. More often, we understand it as certain cells that just wont stop growing, and are coming together to form this ‘mass’. But a tumor is much more than that. It has structure, it has a collection of cells, it has blood vessels supplying blood, oxygen and nutrients to it. Yes, it is just too darned well organized to be just an extra ‘growth’!

Now as an immunologist, when I say ‘Immune organ’ I think about the Bone marrow, thymus, spleen and lymph nodes (Yes, if you ever wondered what the spleen did, here’s your answer ;)) But a tumor? It was farthest away from my definition of an immune organ in my mind. But again, what is the definition of an immune organ? 1) It has a structure that allows for compartmentalization of the different immune cell subsets present in it 2) It facilitates interaction between different immune cell subsets to bring about a desirable immune response (mostly) 3)  It produces chemical attractants called chemokines to attract immune cells 4) It needs to be well vascularized and needs plenty of blood supply to provide nourishment for all the cells housed inside.

Studies published in field have described the presence of Tertiary lymphoid structures (TLSs) inside a tumor – a structure that agrees with definition (1) above. If you see my description of a tumor earlier, point  (4) is met as well. Tumor cells also express chemokine and chemokine receptors to attract immune cell subsets to them. A wide range of immune cell types have been found in tumors – T cells, B cells, Tregs, dendritic cells, myeloid cells and innate immune cells. Condition (3) – satisfied. Now why why would a tumor have an extensive mechanism (and structure) in place to recruit immune cells? Isn’t it counter-intuitive? Will the immune cells not, in turn, destroy the tumor? Look at point (2) above . Bring together immune cells to facilitate a desirable immune response. A. Desirable. Response. Desirable response for whom? The tumor, of course! My previous post was all about how tumors manipulate the immune system so they can escape detection and immune attack. So I will not elaborate on that anymore. But an important addition to be made here is that not does does the tumor evade the immune response, it also manipulates immune cells (and chemokines produced by them) to facilitate angiogenesis (formation of new blood vessels) so it can continue to grow! With that, my arguments complete. A tumor could be a classified as a modified/ sophisticated immune organ. Only, it does it own bidding, not our body’s. Therein lies the biggest difference between OUR immune organs and a tumor.

What this means: In my previous post, I wrote about the coming-of-age of immunotherapies for cancer. But with a tumor possessing a sophisticated structure and an entire arsenal of immune cells, will a single modular therapy, targeting one antigen or cell type be enough? Combinational therapies are starting to gain recognition in scientific circles and seem to be the the next big thing. They involve combining 2 modalities of treatment – chemotherapy+ immunotherapy, immunotherapy + radiation, 2 different modalities of immunotherapy etc. I hope to write about combinational therapies in a more detailed post in the future. But the main point is that when your enemy is as formidable as cancer, I believe that you need to have more than one trick up your sleeve!

Cancer Immunotherapy – 2013 Science Breakthrough of the year

Science magazine just declared cancer immunotherapy as the breakthrough of the year (1). Being an immunologist, and cancer immunotherapy being the topic of my PhD research, I could not be more excited.

Cancer immunotherapy involves harnessing the body’s immune system, especially the immune system’s ‘soldiers’ known as T cells to destroy the tumor. In the late 1980s, scientists discovered that tumors were smart enough to employ mechanisms to evade detection by the immune system (2). A prominent mechanism was inhibiting T cell function (either by blocking stimulatory receptors on T cells or by engaging alternate receptors that would inhibit T cell function). Manipulating this immunosuppression mediated by the tumors, and turning it around, formed the basis for hundreds of research and pre-clinical studies.  Several research groups have dedicated the last decade or more to discovering specific molecules on T cells that could be manipulated. The idea was that by preventing the interaction between the tumor and the T cells, or by inhibiting the ‘inhibitory receptors’ on T cells, you could unleash an immune attack on the tumors. These studies gave rise to multiple drug targets, importantly the antibodies to the molecules CTLA-4 and PD-1 (A.K.A CTLA4-Ig and anti-PD-1). These antibodies have shown extremely promising results in clinical trials. Indeed, it seems like it is only a matter of time before these antibodies are approved by the FDA and can be bought off the shelves.

Antibodies targeting specific molecules are not the only approach in cancer immunotherapy. Some groups have isolated T cells from the blood of cancer patients, genetically engineered them, and re-infused them back into the patients. The Chimeric Antigen Receptor (CAR) therapy commands a special mention in this area. Here’s how it works: Every kind of tumor cell expresses a unique protein (antigen) on it. The CAR therapy employs isolating the T cells from cancer patients, engineering them to express a receptor highly specific for that particular antigen and transferring the T cells back into the patient. Dr. Steven Rosenberg’s group at the National Cancer Institute (NCI) and Dr. Carl June’s group at U Penn have done pioneering work in this field.  I was fortunate enough to visit Dr. Rosenberg’s facility last spring and what I saw there amazed me. First off, the patients being recruited to these experimental studies were all patients with poor prognosis – they were probably given 6 months to live (if even) and all other standard methods of treatment had failed on them. Signing up for this trial was a last resort for most of these patients. I heard stories about tumors vanishing three days after treatment, orange-sized tumors shrinking down to the size of a grape, and body scans that left you gaping in astonishment and made you wonder whether the tumors were just a figment of your imagination! Definitely, it looked like there was a cure for cancer after all!

What this means (the section where I get to the crux of the matter): To be considered the breakthrough of the year by Science means that cancer immunotherapy is getting some serious attention from the medical research community. Long time coming, I would say. The various successful clinical trials and thousand of lives saved attest to the fact that indeed, cancer immunotherapy can be viewed as a serious therapeutic alternative. However, is it time to bring immunotherapy into the clinic as a standard method of treatment for cancer patients? Not so fast.  Tumors often express the body’s own antigens on them, just in a modified or increased manner. Tumors are after all, our own cells that have gone awry. One of the biggest critique immunotherapy receives is that the genetically engineered T cells, may attack the body’s own cells as well, along with the tumor. Autoimmune side effects are not uncommon among immunotherapy recipients. More and more research groups are trying to zero in on tumor antigens and their properties that are unique to the tumor. However, as of now, immunotherapy is far from the clinic, but on the right track.