Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection

Hudson, William Henry; Gensheimer, Julia; Hashimoto, Masao; Wieland, Andreas; Valanparambil, Rajesh M.; Li, Peng; Lin, Jian-Xin; Konieczny, Bogumila T.; Im, Se Jin; Freeman, Gordon J.; Leonard, Warren J.; Kissick, Haydn; Ahmed, Rafi

doi:10.1016/j.immuni.2019.11.002

Cited by 435 publications

(496 citation statements)

References 73 publications

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“…2d). Cells expressing CX3CR1 also highly expressed GZMB and PRF1 , consistent with previous reports that CX3CR1 marks a CD8 + T cell population with superior cytolytic function corresponding to a more differentiated effector phenotype that has been observed in models of chronic infection and other cancers 41–43 . We did not observe a distinct cluster of TCF7 and SLAMF6 dual-expressing progenitor cells previously reported to mediate response to anti-PD-1 therapy in melanoma (Extended Data Fig.…”

Section: Cytotoxic Cell States and Dynamicssupporting

confidence: 91%

“…This population was uncommon in bone biopsies, which instead contained clonally expanded CD8 + T cells with high effector molecule, low exhaustion marker, and CX3CR1 expression. This cell state has previously been linked in model systems and other cancers to high cytolytic activity but poor proliferative potential and a requirement for CD4 help 41–43 . Similar cells have been reported as being unresponsive to PD-L1 blockade, potentially explaining the poor performance of immune checkpoint inhibition in mCRPC bone metastases 1,49 .…”

Section: Discussionmentioning

confidence: 92%

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Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

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Section: Cytotoxic Cell States and Dynamicssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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“…In contrast to the antibody repertoires following LCMV infection, we observed minor differences in the TCR repertoires between acute and chronic cohorts, including the upregulation of the TRBV30 in both spleen/LN and lung repertoires in chronic infection ( Figure 6B) and virus-specific clones restricted to a particular infection cohort ( Figure 6A). Overall, the repertoire structure was strikingly similar between the two infection conditions, further suggesting that phenotypic diversity plays a larger role than CD8 T cell repertoire diversity in response to LCMV infection (Chen et al, 2019;Siddiqui et al, 2019;Hudson et al, 2019). Further experiments investigating the CD4 T cell landscape may provide more apparent differences between the two infection cohorts and Tcf1+ and Tcf1-populations, given both the role of T follicular helper cells in chronic infection and that previous studies performing CD4 depletion have demonstrated that the terminally differentiated Tcf1-population shrinks but not in the proliferation-competent CD8 T cells (Greczmiel et al, 2017;Kanev et al, 2019).…”

Section: Discussionmentioning

confidence: 93%

Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection

Yermanos

Sandu

Pedrioli

et al. 2020

Preprint

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CD8 T cells play a crucial role in providing protection from viral infections. It has recently been established that a subset of CD8 T cells expressing Tcf1 are responsible for sustaining exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. Many of these studies, however, have been performed using T cell receptor (TCR) transgenic mice, in which CD8 T cells express a monoclonal TCR specific for the LCMV glycoprotein. To investigate whether the Tcf1+ and Tcf1-repertoires are naturally composed of similar or different clones in wild-type mice exposed to acute or chronic LCMV infection, we performed TCR repertoire sequencing of virus-specific CD8 T cells, including Tcf1+ and Tcf1populations. Our analysis revealed that the Tcf1+ TCR repertoire is maintained at an equal or higher degree of clonal diversity despite harboring fewer cells. Additionally, within the same animal, there was extensive clonal overlap between the Tcf1+ and Tcf1-repertoires in both chronic and acute LCMV infection. We could further detect these virus-specific clones in longitudinal blood samples earlier in the infection. With respect to common repertoire parameters (clonal overlap, germline gene usage, and clonal expansion), we found minor differences between the virus-specific TCR repertoire of acute and chronic LCMV infection 40 days post infection. Overall, our results indicate that the Tcf1+ population emerging during chronic LCMV infection is not clonally distinct from the Tcf1-population, supporting the notion that the Tcf1+ pool is indeed a fuel for the more exhausted Tcf1-population within the heterogenous repertoire of LCMV-specific CD8 T cells.Yermanos et al.

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“…We observed the emergence of CX3CR1 + cells in the subacute phase even in the absence of TCF-1 + cells or CD4 T cell help. Recent studies have described a similar population and concluded that CX3CR1 + cells constitute a transitional population downstream of TCF-1 + exhausted cells using adoptive transfer (37). It is likely that TCF-1 + cells retain potential to give rise to CX3CR1 + cells as they generate CX3CR1 + cells and terminally differentiated cells upon adoptive transfer or PD-1 blockade.…”

Section: Discussionmentioning

confidence: 96%

Latent Plasticity of Effector-like Exhausted CD8 T cells contributes to memory responses

Raju

Dániel

et al. 2020

Preprint

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Persistent antigen induces a dysfunctional CD8 T cell state known as T cell "exhaustion" characterized by expression of PD-1 and decreased effector functions 1-3 . Nevertheless, dysfunctional CD8 T cells can mediate control of antigen burden which is long-lasting. While significant heterogeneity of exhausted CD8 T cells has been described, the cells which actively proliferate and exert direct viral control have remained elusive. Here, we define subsets of PD-1 + CD8 T cells marked by expression of CX3CR1 exhibit substantial in situ proliferation and expression of granzyme B during chronic infection for the maintenance of the effector pool through self-renewal independently of previously defined stem-like cells. Unexpectedly, the CX3CR1 + CD8 T cells retain plasticity to be reprogrammed to memory cells through expression of TCF-1 and re-gain polyfunctionality. Thus, we define a subset of effector-like exhausted CD8 T cells with capacity to contribute to the memory pool, offering a prime target for novel immunotherapies.

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Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection

Cited by 435 publications

References 73 publications

Transcriptional mediators of treatment resistance in lethal prostate cancer

Transcriptional mediators of treatment resistance in lethal prostate cancer

Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection

Latent Plasticity of Effector-like Exhausted CD8 T cells contributes to memory responses

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