Anti-tumor Immunity and Immune Evasion by Tumor

00:00 So, normal cells. This is normal. Right now normal cells are constantly surveilling their intracellular environment. There are sampling cytosolic proteins and nuclear proteins and all those things processing them into little peptides, about 10 amino acids or so and then expressing them on their cell surface with major histocomptability complex class I, MHC class I. And provided that all the proteins that are in there that are being degraded and sampled and presented ourself, then we have educated the T-cells in our body to leave that alone. That's tolerance. So normal host cells will display multiple different self antigens. But provided we have normal T-cells, there's no response. That's the normal situation. However now if you have a tumor, oh my goodness that tumor is expressing a variety of mutant proteins or new proteins or upregulated proteins that hasn't been seen in the body since it was a developing fetus. All of those proteins are potentially new and antigenic and can be recognized. So again, as the cell goes through its process of sampling its intracellular environment, that milieu, and processing all those different proteins it's going to sample some of those abnormal oncogenic proteins that were never there previously and will express them on their cell surface and now a T-cell comes by and goes "Hey, that's not me anymore, that's something foreign." That immune response is actually part of the normal immune surveillance that helps probably to protect this against a lot of low-grade malignancies. That T-cell recognizes that antigen that has been processed coming from something that's wrong, abnormal tumor, and then it will cause a cytolytic T-cell response with the cytotoxic T-cell, CD8+ T-cell, and we will kill the tumor cell.

02:01 Hooray! And in fact that does happen. In the green box below, there are a variety of oncogenic proteins so they can be mutated RAS, they can be the new fusion protein say from BCR able as in chronic myelogenous leukemia. They can be tumor suppressor gene products such as mutated p53, any mutation in any new protein. They can be new upregulated and increases in certain proteins that we don't normally see a lot of. So in melanomas for example, you may see an over expression of tyrosinase or some of the melanoma-associated antigens, the MART. You can have aberrant expression of fetal proteins. So things that have been turned off since you were in utero and the immune system has never been educated to ignore those. They will not be tolerant of those.

03:01 And then you can have upregulation of those such as carcinoembryonic antigen, something that is present and expressed in the developing fetus but is not expressed in adult tissues. And so that would be a new antigen too that you could potentially respond to. We've talked about the mechanism by which viruses can induce tumor, can cause cancer. And for example in human papillomavirus, HPV, there are new proteins that are elaborated, E6 and E7 proteins that are critical for the carcinogenic process. Those viral proteins are brand new, they're antigenic and that will allow killing of those infected cells.

03:45 And another example is Epstein-Barr nuclear antigen proteins that are expressed during the evolution, the development, the oncogenesis associated with Epstein-Barr virus associated lymphomas. So there are a lot of potential new antigens, but tumors are clever.

04:03 They have ways to evade this. Okay. So how do they do that? Well, in some cases you may not make a lot of mutant proteins or you may not process those in such a way that they can be seen. Well, then that's not going to be very helpful, a T-cell can't respond. So, there's a lack of T-cell recognition of the tumor and that can sometimes happen. More clever than that is you can have mutations in the MHC proteins so they aren't expressed.

04:33 So these tumor cells got abnormal tumor proteins, the blue boxes, but it has turned off its expression of MHC class I, clever tumor. Now all those peptides that are being generated can't be expressed and the T-cell can't see it. There's actually a fail-safe mechanism on that one, I'm just going to mention briefly when you don't express MHC class I, natural killer cells will come in and kill. Okay, little tidbit, but usually there won't be any T-cell recognition. You can have the tumor cell produce immunosuppressive proteins.

05:12 So here, the tumor cell is making an abnormal protein, that's the blue box. It's processing it into little peptides that can be recognized by a T-cell, but at the same time it's cranking out immunosuppressive molecules such as transforming growth factor beta that will inhibit the immune response. And so, everything is working except that the tumor is telling the T-cell "don't make a response." Very clever.