Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE90730 | GEO | 2017/06/19
SECONDARY ACCESSION(S): PRJNA355634
REPOSITORIES: GEO
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Project description:Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRM cells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity. A greater density of TRM cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the 'molecular fingerprint' of tumor-infiltrating CTLs and identify potentially new targets for immunotherapy.
| S-EPMC6036910 | biostudies-literature
Project description:Therapies that boost the anti-tumor responses of cytotoxic lymphocytes (CTLs) have shown promise in the clinic. However, clinical responses to currently available immunotherapeutic agents vary considerably, for which the molecular basis is unclear. To date, unbiased transcriptomic studies of CTLs in human cancers have been performed in whole tumors or cells obtained from peripheral blood or metastatic sites of heavily pre-treated patients. We performed global transcriptional profiling of CTLs in tumors and adjacent non-tumor tissue from treatment-naïve patients with early stage lung cancer to define the molecular features associated with robustness of anti-tumor immune responses. We observed major differences in the transcriptional program of tumor-infiltrating CTLs that are shared across tumor subtypes. Pathway analysis revealed enrichment of genes in cell cycle, T cell receptor (TCR) activation and co-stimulation pathways, indicating tumor-driven expansion of presumed tumor antigen-specific CTLs. We also observed marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints such as 4-1BB, PD1, TIM3, and their expression was positively correlated with the density of tumor-infiltrating CTLs. Interestingly, transcripts linked to tissue-resident memory cells (TRM), such as CD103, were enriched in tumors containing a high density of CTLs, and CTLs from CD103high tumors displayed features of enhanced cytotoxicity, implying better anti-tumor activity. In an independent cohort of 689 lung cancer patients, we confirmed that patients with CD103high (TRM rich) tumors survived significantly longer. In summary, we define the molecular fingerprint of tumor-infiltrating CTLs at the site of primary tumor and identify a number of novel targets that may be important in modulating the magnitude and specificity of anti-tumor immune responses in lung cancer.
2017-06-19 | GSE90729 | GEO
Project description:Therapies that boost the anti-tumor responses of cytotoxic lymphocytes (CTLs) have shown promise in the clinic. However, clinical responses to currently available immunotherapeutic agents vary considerably, for which the molecular basis is unclear. To date, unbiased transcriptomic studies of CTLs in human cancers have been performed in whole tumors or cells obtained from peripheral blood or metastatic sites of heavily pre-treated patients. We performed global transcriptional profiling of CTLs in tumors and adjacent non-tumor tissue from treatment-naïve patients with early stage lung cancer to define the molecular features associated with robustness of anti-tumor immune responses. We observed major differences in the transcriptional program of tumor-infiltrating CTLs that are shared across tumor subtypes. Pathway analysis revealed enrichment of genes in cell cycle, T cell receptor (TCR) activation and co-stimulation pathways, indicating tumor-driven expansion of presumed tumor antigen-specific CTLs. We also observed marked heterogeneity in the expression of molecules associated with TCR activation and immune checkpoints such as 4-1BB, PD1, TIM3, and their expression was positively correlated with the density of tumor-infiltrating CTLs. Interestingly, transcripts linked to tissue-resident memory cells (TRM), such as CD103, were enriched in tumors containing a high density of CTLs, and CTLs from CD103high tumors displayed features of enhanced cytotoxicity, implying better anti-tumor activity. In an independent cohort of 689 lung cancer patients, we confirmed that patients with CD103high (TRM rich) tumors survived significantly longer. In summary, we define the molecular fingerprint of tumor-infiltrating CTLs at the site of primary tumor and identify a number of novel targets that may be important in modulating the magnitude and specificity of anti-tumor immune responses in lung cancer.
2017-06-19 | GSE90728 | GEO
Project description:Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer
| PRJNA355634 | ENA
Project description:Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.
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Project description:High numbers of tissue-resident memory T (TRM) cells are associated with better clinical outcomes in cancer patients. However, the molecular characteristics that drive their efficient immune response to tumors are poorly understood. Here, single-cell and bulk transcriptomic analysis of TRM and non-TRM cells present in tumor and normal lung tissue from patients with lung cancer revealed that PD-1-expressing TRM cells in tumors were clonally expanded and enriched for transcripts linked to cell proliferation and cytotoxicity when compared with PD-1-expressing non-TRM cells. This feature was more prominent in the TRM cell subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex vivo and also reflected in their chromatin accessibility profile. This PD-1+TIM-3+ TRM cell subset was enriched in responders to PD-1 inhibitors and in tumors with a greater magnitude of CTL responses. These data highlight that not all CTLs expressing PD-1 are dysfunctional; on the contrary, TRM cells with PD-1 expression were enriched for features suggestive of superior functionality.
| S-EPMC6719422 | biostudies-literature
Project description:T cell memory is critical in controlling infection and plays an important role in anti-tumor responses in solid cancers. While effector memory and central memory T cells circulate and patrol non-lymphoid and lymphoid organs respectively, tissue resident memory T cells (TRM) permanently reside in tissues and provide local protective immune responses. In a number of solid tumors, tumor-specific T cell memory responses likely play an important role in keeping tumors in check, limiting cancer cell dissemination and reducing risk of relapse. In non-small cell lung cancer (NSCLC), a subset of tumor infiltrating lymphocytes (TILs) display phenotypic and functional characteristics associated with lung TRM (TRM-like TILs), including the expression of tissue-specific homing molecules and immune exhaustion markers. High infiltration of TRM-like TILs correlates with better survival outcomes for lung cancer patients, indicating that TRM-like TILs may contribute to anti-tumor responses. However, a number of TRM-like TILs do not display tumor specificity and the exact role of TRM-like TILs in mediating anti-tumor response in lung cancer is unclear. Here we review the characteristics of TRM-like TILs in lung cancer, the role these cells play in mediating anti-tumor immunity and the therapeutic implications of TRM-like TILs in the use and development of immunotherapy for lung cancer.
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Project description:Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant-T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet-regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage.
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Project description:Tissue-resident memory CD8+ T cells (TRMs) confer rapid protection and immunity against viral infections. Many viruses have evolved mechanisms to inhibit MHCI presentation in order to evade CD8+ T cells, suggesting that these mechanisms may also apply to TRM-mediated protection. However, the effects of viral MHCI inhibition on the function and generation of TRMs is unclear. Herein, we demonstrate that viral MHCI inhibition reduces the abundance of CD4+ and CD8+ TRMs, but its effects on the local microenvironment compensate to promote antigen-specific CD8+ TRM formation. Unexpectedly, local cognate antigen enhances CD8+ TRM development even in the context of viral MHCI inhibition and CD8+ T cell evasion, strongly suggesting a role for in situ cross-presentation in local antigen-driven TRM differentiation. However, local cognate antigen is not required for CD8+ TRM maintenance. We also show that viral MHCI inhibition efficiently evades CD8+ TRM effector functions. These findings indicate that viral evasion of MHCI antigen presentation has consequences on the development and response of antiviral TRMs.
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Project description:Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.
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