Tumor elimination requires simultaneous expression of both class I and II neo-epitopes

The most tumors express mutant epitopes that could be detected by T cells. According to current paradigm, CD4+ T cells provides help to CD8+ T cells that in turn attack tumors. As tumor cells ordinarily express class I recognized by CD8+ T cells but not class II molecules recognized by CD4+ T cells, primary focus on CD8+ T cell epitopes made a lot of sense. But what about CD4+ T cell 'help' to CD8 T cells? 

Indeed, a new 'classically-done' immunology study from Robert Schreiber's lab clearly showed that irrespective class II expression, tumor cells must express both CD8+ and CD4+ T cell neo-epitopes to achieve efficient local tumor control following immunotherapy.

As a starting point, they used nonimmunogenic oncogene-driven KP9025 sarcoma cells (KP), which lack mutational neoantigens. Next they re-expressed in KP cells 2 mutant epitopes, one for class I, mLAMA4, and another for class II, mITGB1 (identified using a hidden Markov model (HMM)-based MHC binding predictor the authors claim is better than other available algorithms). 

 

A mutant but not wild-type version of ITGB1 was detected by CD4+ TILs.

  

Next, the authors showed that only KP tumors expressing both neo-epitopes but not single expressors, could be eliminated by T cells following immunotherapy.

  

As expected, presence of CD4+ T cell epitope enhanced CD8+ T cell response.

Interestingly, both class I and II  neo-epitopes must be expressed by the same tumor to mediate protection when used as immunized agents (mixing of single expressor tumors was not enough).

And notably, expression of both class I and II neo-epitopes were necessary to mediate efficient local tumor control (single expressor tumors were resistant against CD8+ or CD4+  T cells)

In summary, this is a simple, easy to follow experments that indicate the authors' thought process.  It shows that CD4+ T cells 'help' to CD8+ T cells are required both at priming and as well as at effector stage. It is not clear if it is simply a quantitative or rather qualitative issue. It is not known either whether CD4+ T cells do something directly against tumor beyond simply helping CD8+ T cells here. 

posted by David Usharauli

MHC class II epitope presentation modulates microbiota and protects against autoimmunity

It is not clear how exactly microbiota modulates host's immune system. Evidence are largely based on empirical observations and nonspecific factors secreted by microbiota. Presently very little is known if microbiota-immune system interface is also controlled at the level of antigen-specific adaptive immune system.    

 

New study from Diane Mathis lab published in PNAS suggests it may be the case.

 

Her lab studies human type I diabetes (T1D) mouse model known as NOD. NOD mice lack MHC II allele, Eα. In this study they used NOD mice expressing Eα, referred as Eα16/NOD. In mating experiments, they noticed when Eα was expressed by female but not by male parent, baby mice with NOD genotype showed significant protection from developing T1D, suggesting protection was transmitted vertically from Eα16/NOD mother to NOD pups. Interestingly, this protection was lost when pregnant mothers (dams) were treated with antibiotics pointing towards role of microbiota.

Experiments with germ-free sterile mice confirmed this observation.

In summary, this study showed that MHC class II [epitope] presentation modulates composition of microbiota in such a way to harbor species protective against T1D. Again, the authors were unable to specifically pinpoint any specific mechanism of protection, though they reported increase in Foxp3+ Treg numbers in Eα16/NOD mice compared to NOD (but found no difference in microbiota bound to IgA between mouse strains). It is likely that epitope presentation at the level of adaptive CD4 T cells contributed to development of protective environment.

posted by David


    

 

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