Biology subjects

Palmer, D. C.

Publications and source records attributed to Palmer, D. C..

3 recordsLinked to original sources

bioRxiv2024

Initial TCR Signal Strength Imprints GATA3 and Tbet Expression Driving T-helper Cell Fate Decisions

With the exception of the T-helper 2 (Th2) subset, cytokine driven pathways provide a robust mechanistic explanation for the observed outcomes of CD4+ T-cell differentiation. Using a quantitative model of activation, we studied the integration of TCR-signal-strength with cytokine signalling during Th2 differentiation. Upon the initial activation of Th-naive cells, TCR signalling was found to set early expression levels for the master regulators of differentiation Tbet and GATA3, independent of the presence of polarizing cytokines. Subsequently cytokine stimuli modulated transcription factor (TF) expression levels to tune the outcome of differentiation. Here, weak TCR signalling was sufficient to drive the early upregulation of GATA3 and induce Th2 differentiation, in an IL-4 independent manner. Th1 differentiation was however shown to require additional cytokine signalling input, either in the form of autocrine IFN{gamma} or exogenous IL-12. Using mathematical modelling we demonstrate that T-helper differentiation occurs along a continuum of states. Set by the relative co-expression of regulatory TFs, where effector cytokine production is controlled in a probabilistic manner determined by the relative levels GATA3 and Tbet expressed. Together, our data indicate TCR signalling inputs drive an early bifurcation in the T-helper differentiation pathway. Together, the integration of TCR signal strength with cytokine inputs act as a mechanism for the detection of immuno-evasive parasitic infections, whilst providing an additional checkpoint to prevent aberrant Th1 associated immunopathology.

immunology↗

bioRxiv2020

Internal checkpoint regulates T cell neoantigen reactivity and susceptibility to PD1 blockade

While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen-expressing tumors, their adoptive transfer fails to consistently elicit durable tumor regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX in TIL senescence. We found these markers were inversely expressed to Cytokine-Induced SH2 protein (CISH), a negative regulator of TCR signaling and tumor immunity in mice. To evaluate the physiological role of CISH in human TIL we developed a high-efficiency CRIPSR-based method to knock out CISH in fully mature TIL. CISH KO resulted in increased T cell receptor (TCR) avidity, tumor cytolysis and neoantigen recognition. CISH expression in the tumor resections correlated with TIL inactivity against p53 hotspot mutations and CISH KO in TIL unmasked reactivity against these universal neoantigens. While CISH KO resulted in T cell hyperactivation and expansion it did not alter maturation, perhaps by preferential PLC{gamma}-1 and not AKT inhibition. Lastly, CISH KO in T cells increased PD1 expression and the adoptive transfer of Cish KO T cells synergistically combines with PD1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. These data offer new insights into the regulation of neoantigen recognition, expression of activation/exhaustion markers, and functional/maturation signals in tumor-specific T cells.

immunology↗

bioRxiv2019

Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy

All current highly effective anti-tumor immunotherapeutics depend on the activity of T cells, but tumor cells can escape immune recognition by several mechanisms including loss of function in antigen presentation and inflammatory response genes, expression of immunomodulatory proteins and an immunosuppressive tumor microenvironment. In contrast, the comprehensive identification of strategies that sensitize tumor cells to immunotherapy in vivo has remained challenging. Here, we combine a two-cell type (2CT) whole-genome CRISPR-Cas9 screen with dynamic transcriptional analysis (DTA) of tumor upon T cell encounter to identify a set of genes that tumor cells express as an active defense against T cell-mediated killing. We then employed small molecule and biologic screens designed to antagonize gene products employed by tumor cells to actively defend against T cell-mediated tumor destruction and found that the inhibition of BIRC2, ITGAV or DNPEP enhanced tumor cell destruction by T cells. Mechanistically, we found that BIRC2 promoted immunotherapy resistance through inhibiting non-canonical NF-{kappa}B signaling and limiting inflammatory chemokine production. These findings show the path forward to improving T cell-mediated tumor destruction in the clinic.

immunology↗