CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer

Zander, Ryan; Schauder, David M.; Xu, Gang; Nguyen, Christine; Wu, Xiaopeng; Zajac, Allan; Cui, Weiguo

doi:10.1016/j.immuni.2019.10.009

Cited by 489 publications

(530 citation statements)

References 52 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: 93%

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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: 93%

Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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“…However, the conversion from TCF-1 + cells to CX3CR1 + cells may only slowly occur during the chronic phase of antiviral response or in the tumor microenvironment without PD-1 blockade or adoptive transfer, given that we observe persistence of fate-mapped cells and active proliferation. Together with the slow conversion of Cx3cr1 fatemapped cells to TIM3 + CX3CR1cells during the chronic phase, which was also reported by another recent paper 41 , CX3CR1 + cells could constitute an independent lineage that is sustainable by at least limited self-renewal 41 .…”

Section: Discussionsupporting

confidence: 64%

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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“…Consequently, the maintenance of these T RM cells requires persistent MHC I-dependent stimulation at the memory stage 40 , similar to those of exhausted CD8 + T cells 69 . Notably, CD4 + T cell help in the form of IL-21 has been recently demonstrated to sustain those PD-1-expressing CD8 + T cells during chronic viral infection and tumor growth 71 . Thus, CD4 + T cell help and IL-21 signaling may be specifically required for maintaining the survival of lung CD8 + T RM cells receiving persistent low levels of in situ antigenic stimulation.…”

Section: Discussionmentioning

confidence: 99%

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

Son

Cheon

et al. 2020

Preprint

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32The roles of CD4 + T helper cells (TH) in shaping localized memory B and CD8 + T cell immunity 33 in the mucosal tissues are largely unexplored. Here, we report that lung TH cells provide local 34 assistance for the optimal development of tissue-resident memory B (BRM) and CD8 + T (TRM) 35 cells following the resolution of primary influenza virus infection. We identify a population of 36 tissue-resident CD4 + TH (aka TRH) cells that co-exhibit follicular T helper (TFH) and TRM cell 37 features and mediate local help of CD4 + T cells to B and CD8 + T cells. Optimal TRH cell 38 formation requires lung B cells and transcription factors involved in TFH or TRM development. 39Further, we show that TRH cells deliver local help to B and CD8 T cells through CD40L and IL-40 21-dependent mechanisms. Our data have uncovered a new tissue-resident TH cell population 41 that is specialized in assisting the development of mucosal protective B and CD8 + T cell 42 responses in situ.

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CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer

Cited by 489 publications

References 52 publications

Transcriptional mediators of treatment resistance in lethal prostate cancer

Transcriptional mediators of treatment resistance in lethal prostate cancer

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

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses

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CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer

Cited by 489 publications

References 52 publications

Transcriptional mediators of treatment resistance in lethal prostate cancer

Transcriptional mediators of treatment resistance in lethal prostate cancer

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

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

Contact Info

Product

Resources

About

Tissue-resident CD4⁺T helper cells assist protective respiratory mucosal B and CD8⁺T cell memory responses