Monday, April 17, 2017

HPV+ cancers express non-viral neo-antigens targeted during adoptive immunotherapy

Human papillomavirus can induce epithelial cancers. HPV oncoproteins (E6, E7) are thought to be clinically-relevant antigenic targets for antigen-specific immunotherapy. 

New study in Science showed however that in patients "with HPV+ metastatic cervical carcinoma who experienced complete cancer regression" after adoptive immunotherapy, T cells target cancer-specific mutated neo-antigens, not just viral antigens.

These results indicate that HPV+ cancer patients could benefit from adoptive transfer of T cells specific for non-viral oncoproteins  (though it is not clear from this study whether non-viral tumor neo-antigen specific T cells or HPV oncoprotein specific T cells were responsible tumor regression).

David Usharauli

Sunday, April 9, 2017

The role of LAG3 in Tregs and how infection modulates immune response to dietary antigens

Lymphocyte activation gene 3 (LAG3) is the most recent checkpoint inhibitor to be targeted in the clinic. LAG3 has been shown to dampen T cell activity. For instance, diabetic-prone mice deficient in LAG3 exhibit accelerated autoimmune diabetes with 100% of KO mice developing it. As Foxp3+ regulatory T cells express LAG3 it was thought that it played a role in Treg activity.

Surprisingly, however, according to new study mice with Treg-specific LAG3 deficiency showed improved rather than diminished protection against development of autoimmune diabetes. 

This unexpected outcome requires rethinking the role LAG3 within immune system. Systemic inhibition of LAG3 by blocking antibodies could enhance tumor progression, for example, by stimulating tumor-infiltrating Tregs.

Another paper, however, with ambitious title I read this week fell flat upon examining actual data. Its objective was to examine how viral infection could modify host's immune response to dietary antigens and lead to celiac disease. According to paper "celiac disease (CeD) is a complex immune disorder with an autoimmune component in which genetically susceptible individuals expressing the human leukocyte antigen (HLA) DQ2 or DQ8 molecules display an inflammatory T helper 1 (TH1) immune response against dietary gluten present in wheat".

To replicate hypothetical scenario that could lead to celiac disease, the authors infected mice with reovirus and simultaneously gave them nominal antigen, OVA, as a dietary antigen. As virus induced inflammation, it led to reduced numbers of Foxp3+ Tregs and parallel increase in Th1 transcription factor, T-bet+ T cells specific for dietary antigen.

The authors concluded that viral infection could modify body's response to dietary antigens. However, such conclusion is premature here as it is not obvious that those T cells that were destined to become Foxp3+ regulatory T cells were actually diverted into Th1 lineage. It is not clear either what would be the outcome of dietary antigen exposure once viral infection is cleared or how long the effect of viral infection modifies a physiological response to dietary antigens.

David Usharauli


Thursday, March 23, 2017

Mantle-cell lymphoma neoantigens are derived from immunoglobulins

This week Nature published new study that could explain why B cell-derived lymphomas are not easily rejected by body's immune system. It also highlights some of the obvious forgetfulness regarding basic immunology concepts.  

In this paper, research group from Stanford analyzed neo-antigenic burden in untreated mantle-cell lymphoma, a subtype of B-cell non-Hodgkin lymphoma. Rather than simply doing whole exome-sequencing of lymphoma DNA to identify tumor associated non-synonymous somatic mutations, the authors focused on direct proteomic analysis of cancer MHC ligands, epitopes, by liquid chromatography and tandem mass spectrometry (LC–MS/MS)

Interestingly, though the authors found 13–175 non-synonymous somatic mutations per patient within genes known to mutate in mantle-cell lymphoma, such as TP53, CCND1, none of the mutated neo-epitopes from these genes were actually presented by MHC molecules. Only exception were neo-antigens derived from immunoglobulin (Ig) genes themselves. Surprise, surprise! 

As the authors wrote "presentation of variable-region peptides by MHC-II suggests that Ig neoantigen recognition by CD4 does not inhibit lymphoma development." Why that could be the case? As we know, when B cell responds to antigen it undergoes hypermutations within its Ig variable regions. In essence, every responding B cell generates neo-antigens within its Ig molecules. These are antibodies the body is using to defend against pathogens. Obviously Ig hypermutated B cells (and memory B cells or plasma cells derived from such B cells) are not ordinarily rejected by body's own immune system. It is strange that the authors did not mention this obvious contradiction.  

David Usharauli