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Extrinsic C5a Activation Regulates Squamous Carcinogenesis and Limits Clonal T Cell Responses to Chemotherapy (Blood)

ABSTRACT: In the K14-HPV16 transgenic mouse model of squamous carcinogenesis, activation of C5a receptor (C5aR1) in early neoplastic tissues fosters protumorigenic properties of C5aR1+ mast cells and macrophages, and in turn, suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5a receptor (C5aR1) with a peptide antagonist improved efficacy to paclitaxel chemotherapy associated with CXCR3-dependent CD8+ T cell activation. To investigate the effects of combination therapy on the T cell repertoire, we performed deep sequencing of the complementarity-determining region (CDR) 3 of the T cell receptor (TCR)b chain in matched tumor lysates and peripheral blood mononuclear cells (PBMCs). Intratumoral TCRβ clonotypes were hyperexpanded and increasingly detected in matched peripherally-expanded T cell populations, thereby implicating antigen-dependent peripheral priming in response to systemic C5aR1 inhibition.

ORGANISM(S): Mus musculus

PROVIDER: GSE112321 | GEO | 2018/11/28

REPOSITORIES: GEO

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Project description:The complement system is part of the innate immune system that works to clear pathogens and cellular debris. In the central nervous system (CNS) complement activation can promote synaptic pruning clearance of neuronal blebs recruitment of phagocytes and protection from pathogens. However in a neuropathologic environment complement activation may contribute to inflammatory pathways neuronal dysfunction and in the Alzheimer’s disease (AD) brain cognitive decline. If complement activation proceeds to the cleavage of C5 and thus generation of C5a engagement of C5a with the receptor C5aR1 can instigate a feed-forward loop of inflammation injury and neuronal death thus making this molecule a potential target for modulation in AD therapeutics. The Arctic (Arc) AD mouse model known to rapidly accumulate fibrillar amyloid plaques was crossed to a model that lacks the receptor for C5a (ArcC5aR1KO) or to a transgenic mouse that generates C5a under the GFAP promoter (ArcC5a+). ArcticC5a+ mice showed accelerated loss of spatial memory compared to Arc mice. While eliminating C5aR1 did not alter amyloid plaque accumulation in this AD model C5aR1KO delayed or prevented the expression of important AD-associated genes in the hippocampus indicating a separation between those genes induced by amyloid plaques and those influenced by C5a-C5aR1 signaling. C5ar1 deletion also reduced/delayed the expression of select pan-reactive and A1 reactive astrocyte genes. ArcC5aR1KO showed delayed expression of genes enriched for biological processes that are significant in the AD context such as regulation of inflammatory signaling microglial cell activation astrocyte migration and lysosome pathway. Interestingly overexpression of C5a also delayed the increase of some AD- complement and astrocyte-associated genes perhaps mediated by C5aR2 and emphasizing the importance of selectively suppressing C5aR1. Immunohistochemical investigation further confirmed that modulation of C5a-C5aR1 either delayed or reduced some reactive microglial markers in the Arc hippocampus including CD11b and CD11c. These results suggest that C5a-C5aR1 signaling in the context of AD largely exerts its effects by suppressing those microglial activation pathways that accelerate disease enhancing pathways. Given the highly focused modulation of a common driver of neurotoxicity pharmacological inhibition of this C5aR1 signaling pathway is a promising therapeutic strategy to treat AD.

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Extrinsic C5a Activation Regulates Squamous Carcinogenesis and Limits Clonal T Cell Responses to Chemotherapy (Blood)

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