PD-1 expression on tumor-infiltrating T cells does not correlate with antigen-specific response

Patients selection [stratification] and then monitoring for immunotherapy effectiveness is part of precision medicine. In humans, especially, when determination of cancer neo-antigens is not always feasible, clinical diagnostic tests are focused on surrogate markers to tell whether patient has a tumor antigen-specific immune response. More recently, PD-1 has become one of such surrogate markers. However it is not clear whether expression of PD-1 could truly correlate with T cell antigen-specific response.

New paper in Journal Immunology provided data to suggest that at least in mice tumor models PD-1 expression does not correlate with T cell antigen-specific response within tumor tissue.

For example, they showed that OT-I CD8 T cells would express PD-1 irrespective whether tumor expresses or not specific OVA antigen. In contrast, Nur77 (part of TCR signaling) expression correlated with tumor neo-antigen expression. 

This study indicate that diagnostic tests measuring PD-1 expression on tumor-infiltrating T cells may over-estimate tumor antigen-specific immune response and lead to unpredictable outcomes during antibody immunotherapy.

David Usharauli

Division of labor among thymus-derived Foxp3+ regulatory T cells

This week Nature Immunology published study that showed another level of "division of labor" among regulatory Foxp3+ T cells (Tregs). The authors revealed presence of two types of thymic Tregs defined by expression of three receptors, GITR, PD-1 and CD25 (GITR^hiPD-1^hiCD25^hi and GITR^loPD-1^loCD25^lo Tregs cells) that displayed non-overlapping functionality.

Specifically, only GITR^loPD-1^loCD25^lo Tregs cells prevented colitis development in adoptive transfer experiment by converting responding naive T cells into induced Tregs.

On the other hand, only GITR^hiPD-1^hiCD25^hi Tregs cells prevented uncontrolled proliferation of endogenous T cells when transferred into Treg-depleted host.

In summary, this study revealed that even among thymus-derived natural Tregs there is a division of labor. It is possible that difference between these two types of thymic Tregs is also related to their differential migration pattern as it was suggested by one recent study on KLF2.

David Usharauli

IL-4R mutation drives IL-17 dominant asthma phenotype

Asthma represents a dysregulated immune response to antigens that normally do not produce clinically-detectable immune responses. Ordinarily asthma response was regarded as classical Th2 class response with dominant IL-4/IL-13/eosinophil axis. However, for past 10 years, since the discovery of Th17 cells, scientists started to find a separate subtype of asthma dominated by IL-17/neutrophil axis. 

New paper in Nature Medicine pinpointed one molecular mechanism that underlie Th2→Th17 switch in asthma. It showed that a single amino acid mutation in IL-4Rα introduces instability in regulatory T cell lineage leading to Th17 induction.

Initially, the authors observed that mice with a glutamine (Q)-to-arginine (R) substitution at amino acid residue 576 of IL-4Rα (Il4ra^R576 mice) develop more severe experimental asthma in response house dust mite allergen.

In vitro culture of conventional or induced regulatory T cells derived from mice on Il4ra^R576 background showed exaggerated IL-17 expression in response to TGFβ1 and IL-4.

Lineage tracing analysis revealed instability of regulatory T cell lineage and their differentiation into IL-17 producing cells (ex-Tregs).

Indeed, when Tregs were rendered incapable to differentiate into IL-17 producing cells in Foxp3^YFPCreRorc^Δ/Δ mice, severity of asthma was reduced.

In summary, this study showed that genetic mutation in IL-4Rα introduces instability in Treg lineage and leads to IL-17 dominant asthma phenotype. Such asthma conversion is expected to be sensitive to anti-IL6 therapy.

David Usharauli