Skin resident memory CD8+ T cells, stimulated by vaccines, protect against melanoma!!!!

I have long hoped vaccines would play a positive role in melanoma treatment!!  Heck, I was a rattie in one of the arms of my nivo trial that included peptide vaccines.  Here is one of my latest posts on the topic:  ASCO 2018!!! We'll start with melanoma vaccines....and a story!

To sum up that post ~ I, along with my fellow ratties, were injected with 6 painful peptide vaccines (as in, they were administered as an injection into our thighs) every 2 weeks for 6 months along with our intravenous infusion of nivolumab.  It turned out that our particular vaccine did us no good.  It is even possible that the injections "sequestered" our helpful CD8+ T cells at the site of the injections.  There is some evidence that rather than revving up our fighting T cells and having them go attack our melanoma, the vaccines simply attracted them, perhaps even fired them up, but then the little suckers just lazed about at the vaccine sites, like camels at an oasis.  (Do camels do that?  I don't really know.)  Anyhow, additional abstracts about vaccine hopes and dreams and scams are included in the post, but... there is also this:

Dendritic cell vaccine induces antigen-specific CD8+ T cells that are metabolically distinct from those of peptide vaccine and is well-combined with PD-1 checkpoint blockade. Nagoaka, Hosoi, Lino, et al.Oncoimmunology. 2017 Nov 2.

The success of immune checkpoint blockade has unequivocally demonstrated that anti-tumor immunity plays a pivotal role in cancer therapy. Because endogenous tumor-specific T-cell responsiveness is essential for the success of checkpoint blockade, combination therapy with cancer vaccination may facilitate tumor rejection. To select the best vaccine strategy to combine with checkpoint blockade, we compared dendritic cell-based vaccines (DC-V) with peptide vaccines for induction of anti-tumor immunity that could overcome tumor-induced immunosuppression. Using B16 melanoma and B16-specific TCR-transgenic T-cells (pmel-1), we found that DC-V efficiently primed and expanded pmel-1 cells with an active effector and central memory phenotype that were not exhausted. Vaccine-primed cells were metabolically distinct from naïve cells. DC-V-primed pmel-1 cells contained the population that shifted metabolic pathways away from glycolysis to mitochondrial oxidative phosphorylation. They displayed better effector function and proliferated more than those induced by peptide vaccination. DC-V inhibited tumor growth in prophylactic and therapeutic settings. Only DC-V but not peptide vaccine showed augmented anti-tumor activity when combined with anti-PD-1 therapy. Thus, DC-V combined with PD-1 checkpoint blockade mediates optimal anti-cancer activity in this model.

Here, in a petri dish, researchers treated melanoma cells with a dendritic vaccine and a peptide vaccine.  They found that only the dendritic vaccine (NOT the peptide vaccine, further corroborating what we real live ratties found in my study) helped increase anti-tumor activity when combined with anti-PD-1 therapy.  Okay.  As far as that goes....

Okay.  I think this is the perfect place to utilize a phrase I created in my childhood, "What's so about that?????"  Well, maybe nothing.  But now, there's this - (and a link to the entire article if you are so inclined):

Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma

Vaccination-induced skin-resident memory CD8⁺ T cells mediate strong protection against cutaneous melanoma. Gálvez-Cancino, López, Menares, et al.  Oncoimmunology. 2018 Mar 19.


Memory CD8⁺ T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8⁺ T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8⁺ T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

You may be thinking, "Interesting, I guess!  But, what's so about that????"

Well, the notation "intradermal" might just be the thing.  It seems from this research that in order to elicit the response Galvez and Lopez are talking about, the vaccine had to mess with the SKIN!!!  Not just be stuck in the body else wise.

Now, give me a minute here.  Remember the mad scientist I live with???  He has been postulating a theory about how triggering a response in dendritic cells and CD8+ T cells that LIVE IN THE SKIN might be the ticket to stimulating the development of vitiligo and thereby a good response AGAINST melanoma for years!

Remember this?  Itching and vitiligo associated with progression free survival after Pembro/Keytruda???!

And this from 2014:  Vitiligo and melanoma  Which includes this commentary:  What I think this says is:  The CD8+ T cells that cause vitiligo, promote response to melanoma.  But, we don't know how. So...the researchers checked a certain type of T cell in mice with no thymus (so the mice couldn't use that part of the process to induce vitiligo) and even so, the active T cells continued to produce vitiligo and protection against melanoma.....and they don't know why!

This from 2015:  Vitiligo....a good prognostic indicator for melanoma!  Which, for the purposes of this discussion is most important for this pic and the commentary beneath it ~

"Vitiligo initiation at site of surgery."  The vitiligo in this poor actual rattie started WHERE THE SKIN WAS CUT!!!!!!!!!!!!!!!!!!!!!

And finally - if you are still with me!!! - there is this from 2011:  Anti-PD-1 is still kicking....

Here, I note:  Apart from that, Brent is developing a rather complicated theory about why which rats, both human and rodent, develop vitiligo, versus those who do not, and thereby have a more positive outcome in regard to their melanoma.  It has to do with the dendritic cells in the skin, their exposure to the melanoma antigen (either from vaccines or from tumor material itself), and the subsequent triggering of the immune response.  I'm telling you...the man is going to win the Nobel Prize for finding the answer to this mess!!  But bottom line, if he's right...does this mean I should be grateful that I am thin, thereby lacking in significant subcutaneous tissue into which the vaccines should have been injected?  Thankful that vaccine material drifted into my dermis either by chance or poor administration techniques by some of the administrators?  Remember Ruthie's dismay when tons of my "Elmer's Glue" came oozing back out of my injection sites? I can't answer those questions, but I'm betting Bentie will figure it out.  I'll just keep reporting.

Okay.  You made it!!!  What all this means, I am not entirely certain.  But, I think research is building more and more of a case about how the skin itself harbors not only evil cutaneous melanoma cells for some of us, but also the key to removing melanoma's protective shroud and killing it!!!  We know that the skin contains:  dendritic cells (of many types!!!), gamma T cells, alpha T cells, CD8+ T cells (specifically the trm [tissue resident memory] cells addressed in this most recent abstract).  We also know that Tissue Resident Memory cells travel up to 2mm per day in the intradermal space.  That's not totally weird or creepy, is it??? TRM's, surveying their territory like a sand shark along the beach, on the look out for tasty minnows or melanoma cells!  Perhaps, the horror of injections that hurt like a booger, then oozed the nasty thick white goo back OUT of the holes poked in my skin, DID make a change in some of my dermal CD8+ Tissue Resident Memory cells.  MAYBE those vaccines did help trigger my vitiligo, as an outward sign of an interior response by my CD8+ T cells against my melanoma.  Maybe the vaccines I was given did not work as initially intended, but did, perhaps, play a role in why I am still here.

Happy 4th.  Here's hoping your dendritic and CD8+ trm cells are busy bees today and every day!!! - c