Intratumoral antigen-signalling traps CD8+ T cells to confine exhaustion to the tumour site (scRNA-Seq)
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ABSTRACT:
PROVIDER: PRJNA1106825 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy advances have been hindered by difficulties tracking the behaviours of lymphocytes following antigen-signalling. Here we present the antigen-receptor signalling reporter (AgRSR) mouse to fate-map lymphocytes responding to antigen at specific times and locations, to determine the behaviour of T cells involved in the tumour immune response. Contrary to reports of ready egress of T cells out of the tumour, we find that intratumoral antigen-signalling traps CD8+ T cells in the tumour. These clonal populations expand and become increasingly exhausted over time. In contrast, antigen- signalled regulatory T cell (Treg) clonal populations readily recirculate out of the tumour. Consequently, intratumoral antigen-signalling acts as a gatekeeper to compartmentalize CD8+ T cell responses – even within the same clonotype, enabling immunity to confine exhaustion to a specific tissue site.
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Project description:Immunotherapy advances have been hindered by difficulties tracking the behaviours of lymphocytes following antigen-signalling. Here we present the antigen-receptor signalling reporter (AgRSR) mouse to fate-map lymphocytes responding to antigen at specific times and locations, to determine the behaviour of T cells involved in the tumour immune response. Contrary to reports of ready egress of T cells out of the tumour, we find that intratumoral antigen-signalling traps CD8+ T cells in the tumour. These clonal populations expand and become increasingly exhausted over time. In contrast, antigen- signalled regulatory T cell (Treg) clonal populations readily recirculate out of the tumour. Consequently, intratumoral antigen-signalling acts as a gatekeeper to compartmentalize CD8+ T cell responses – even within the same clonotype, enabling immunity to confine exhaustion to a specific tissue site.
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Project description:Cooperative interactions among transcription factors are essential for gene transcription. We previously showed that NFAT and AP-1 (Fos-Jun) transcription factors cooperate to promote the effector functions of T cells, but that under conditions where it is unable to cooperate with AP-1, NFAT imposes a negative feedback programme of T cell hyporesponsiveness (“exhaustion”). Here we show that BATF and IRF4 cooperate to counter T cell exhaustion. Overexpression of Batf in CD8+ 42 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumour-infiltrating CAR T cells, increased their production of effector cytokines, decreased their expression of inhibitory receptors and the exhaustion-associated transcription factor TOX, and led to the generation of long-lived memory T cells that controlled tumour recurrence. These responses were dependent on the BATF-IRF interaction, since cells expressing a Batf mutant unable to interact with Irf4 did not survive in tumours and did not effectively delay tumour growth. We suggest that BATF overexpression is a therapeutically viable option for improving the anti-tumour responses of CAR TILs, by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
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Project description:Cooperative interactions among transcription factors are essential for gene transcription. We previously showed that NFAT and AP-1 (Fos-Jun) transcription factors cooperate to promote the effector functions of T cells, but that under conditions where it is unable to cooperate with AP-1, NFAT imposes a negative feedback programme of T cell hyporesponsiveness (“exhaustion”). Here we show that BATF and IRF4 cooperate to counter T cell exhaustion. Overexpression of Batf in CD8+ 42 T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumour-infiltrating CAR T cells, increased their production of effector cytokines, decreased their expression of inhibitory receptors and the exhaustion-associated transcription factor TOX, and led to the generation of long-lived memory T cells that controlled tumour recurrence. These responses were dependent on the BATF-IRF interaction, since cells expressing a Batf mutant unable to interact with Irf4 did not survive in tumours and did not effectively delay tumour growth. We suggest that BATF overexpression is a therapeutically viable option for improving the anti-tumour responses of CAR TILs, by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.
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