Reciprocal T subset-specific tumor protection by RNA vaccine encoding mutant MHC class I and II binding epitopes

Efficacy of solid cancer immunotherapy mostly depends on effector activity of T cells. Initially, CD8 T cells were thought to mediate primary anti-tumor activity. However, for the past 15 years, growing evidence pointed to a stand-alone CD4 T cell role in cancer protection.      

This new paper in journal Nature provided another example of CD4 T cell specific tumor protection. Strangely, the authors' data suggest that in silico generated MHC class I and II binding mutant epitopes reciprocally activated CD4 and CD8 T cell tumor responses, respectively.

Using three different mouse tumor models, the authors showed that surprisingly mice immunized either with MHC class I binding cancer-specific mutant 27-mer peptide + polyI:C or with MHC class I binding mutant epitope-encoding RNAs, generated predominantly CD4 T cell immunogenic response.   

One of the cancer epitope (B16-M30) encoding RNA even induced fully CD4 T cell-dependent 80% protection of cancer bearing mice.

Strangely, when the authors designed RNAs encoding several MHC class II binding mutant epitopes in combination with one class I binding epitope (synthetic RNA pentatope), anti-tumor protection was CD8 T cell-dependent.

Even more strangely, when the authors designed RNA pentatopes with only MHC class II binding epitopes (based on in silico algorithm and expression level), anti-tumor protection was also CD8 T cell-dependent.

In summary, the authors showed that tumors carry multiple (sometimes hundreds) of mutations that can specifically bind to MHC class II molecules. However, why were epitopes selected based on prediction to bind class I molecules induced CD4 T cell-dependent anti-tumor response (and vice versa for class II epitopes and CD8 T cells) are not clear.

David Usharauli    

Research and editorial dissonance in action: beware of 1 year long review process

Here is an example of the paper that should not be published in journal such as Immunity. Its title and abstract sounded interesting. I was always curious how dendritic cells (DCs) could mediate both immunity and tolerance, especially that in both situations DCs should undergo some type of maturation to efficiently interact with T or B cells.

In this article, the authors described mouse model with CD11c-specific inactivation of NF-Kb pathway (Ikbkb^Δitgax). Afterwards, the authors proceeded to analyze cellular and morphological features of this model. Only relevant figures are Fig. 1 and Fig. 7, however even these figures do not support the authors conclusion. To claim that DC-selective deficiency of NF-Kb pathway leads to autoimmune condition, showing spleen and lymph node enlargement or showing antigen specific CD8 T cells expansion and lack of iTreg conversion are insufficient. In fact, the most important finding that antigen-specific CD8 T cells in this model induce skin inflammation are mentioned as data not shown.

I have no idea why editors had allowed publication of this paper. It appears that there was some doubts initially in editors' mind because it took almost full 1 year before the article was accepted for publication. Usually, such a long review process is a strong indication of major weakness in research article. I guess eventually the editors caved in and allowed its publication. Editorial board of journal Immunity needs people with a little bit more integrity and scientific instincts.

David Usharauli

CD8 T effector cells monitor liver tissue with the help of platelet scouts

Liver is a body's chemical detox factory. Several viruses including HBV can infect liver cells called hepatocytes. What is interesting about HBV that it is essentially a non-cytopathic virus in immunocompetent hosts, meaning that it can infect hepatocytes and does no "damage" to it (unlike, for example, influenza virus infection of airway epithelial cells). More likely, due to continuing immunosurveillance of liver tissue by innate immune cells, like NKT and NK cells, liver cells showing obvious abnormalities are quickly eliminated.

But what about adaptive immune system? New study in journal Cell explains how CD8 T_E cells monitor liver for the presence of viral antigens. It appears that CD8 T_E are using platelets for docking on liver endothelial cells to initiate surveillance.

The authors showed that contrary to conventional thinking, initial docking of CD8 T_E cells on liver endothelial cells was antigen-independent in HBV infected hosts.

Next, the authors showed that this particular docking of CD8 T_E cells on liver endothelial cells was independent of known mechanisms involving integrins, selectins or chemokines.

Unexpectedly, initial docking of CD8 T_E cells on liver endothelial cells was reduced by platelet depletion or when adoptively transferred platelets lacked CD44 expression (CD44 interacts with hyaluronan).

The authors showed that after initial Ag-independent docking of CD8 T_E cells on liver endothelial cells via platelets, CD8 T_E cells subsequent liver tissue monitoring and effector function (crawling cessation and IFN-γ secretion) was Ag-dependent events.

In summary, this study described novel mechanism of cell-cell cooperation between CD8 T_E cells and platelets. It is not clear what signals promotes adhesion of CD8 T_E cells to platelets. It is not even clear why platelets are adhering to liver sinusoidal endothelial cells in the first place. Are platelets sensing subtle changes in liver tissue due to non-cytopathic HBV infection?

David Usharauli