Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC

Oja, Anna E.; Piet, Berber; Zwan, David van der; Blaauwgeers, Hans; Mensink, Mark; Kivit, Sander de; Borst, Jannie; Nolte, Martijn A.; Lier, René A. W. van; Stark, Regina; Hombrink, Pleun

doi:10.3389/fimmu.2018.02654

Cited by 99 publications

(102 citation statements)

References 69 publications

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Section: Mainmentioning

confidence: 99%

“…Although CD4 T cells actually outnumber CD8 T cells in barrier tissues, the majority of studies have focused on the requirements for CD8 TRM cell differentiation. In addition, although CD4 T cells are renowned for their substantial plasticity during immune responses, less is known about diversification within the CD4 TRM cell compartment 11,12,13,14,15,16 .Influenza infection induces the differentiation of CD4 TRM cells in the lung, where they are maintained in an antigen and inflammation independent manner 17 . Following a lethal re-challenge, influenza specific CD4 TRM cells rapidly produce effector cytokines and promote both viral clearance and host survival 7 .…”

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confidence: 99%

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Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

Swarnalekha

Schreiner

Litzler

et al. 2020

Preprint

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Influenza is a severe and acute respiratory pathogen, and a significant cause for morbidity, particularly in young children and the elderly. Following influenza infection, clonally expanded T cells take up permanent residence in the lung where they are poised to rapidly respond to challenge infection. The non-circulating status of these tissue resident memory (TRM) cells makes them an attractive target for vaccination. While many studies have characterized CD8 TRM cells, less is known about the heterogeneity and protective capacity of CD4 TRM cells. Here we characterized the dynamics and transcriptional regulation of lung resident CD4 T cells to define a nonlymphoid signature that removes the bias created by the prevalence of Th1 helper cells during viral infection. We identified a novel population of long-lived T resident helper (TRH) cells that requires intrinsic Bcl6 expression for their differentiation. Although TRH cells also depend on B cells, they are generated independently of T follicular helper effector cells in the lymph node. In contrast to lung resident Th1 cells, TRH cells are tightly co-localized with B cells in inducible Bronchus Associated Lymphoid Tissue (iBALT). Deletion of Bcl6 in CD4 T cells prior to heterotypic challenge infection results in redistribution of CD4 T cells outside of iBALT areas and impaired local antibody production. These data highlight lung iBALT as a niche for the homeostasis and survival of TRH cells, and further suggest that vaccination strategies to selectively induce TRH cells can improve protective immunity in the tissue.2 MainSeasonal influenza epidemics are a major cause of global morbidity and mortality. Although annually administered influenza vaccines are among the most widely used in the world, vaccine-elicited neutralizing antibodies offer poor protection against new influenza strains 1 . In contrast, there is evidence that prior influenza infection can accelerate viral clearance after heterotypic infection in both mice and humans 2,3,4,5,6 . Emerging data suggests that the targeted generation of CD4 memory T cells recognizing conserved epitopes from internal viral proteins may form the basis of a universal influenza virus vaccine 7,8 . CD4 memory T cells are induced following immunization or infection and can be recalled to generate secondary effectors during a challenge infection. Several subsets of CD4 memory cells have been described, including central memory (TCM) and effector memory (TEM) cells which circulate through secondary lymphoid and non-lymphoid tissues 9 . More recently, tissue resident memory (TRM) cells that persist in barrier tissues such as lung and skin have been described 10 . Although CD4 T cells actually outnumber CD8 T cells in barrier tissues, the majority of studies have focused on the requirements for CD8 TRM cell differentiation. In addition, although CD4 T cells are renowned for their substantial plasticity during immune responses, less is known about diversification within the CD4 TRM cell compartment 11,12,13,14,15,16 .Influenza i...

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Section: Mainmentioning

confidence: 99%

mentioning

confidence: 99%

Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

Swarnalekha

Schreiner

Litzler

et al. 2020

Preprint

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“…15 In humans, increased CD8 + T cells infiltrating the tumor stroma of NSCLC are a positive prognostic marker, correlating to reduced metastatic risk. 26,27 Accordingly, current immunotherapy strategies are focused on increasing the induction of tumorspecific effector CD8 + T cells, namely immune checkpoint blockade therapy (ICPB), ACT and antitumor vaccination. 26,27 Accordingly, current immunotherapy strategies are focused on increasing the induction of tumorspecific effector CD8 + T cells, namely immune checkpoint blockade therapy (ICPB), ACT and antitumor vaccination.…”

Section: Regulatorymentioning

confidence: 99%

“…17 More recently, resident memory CD8 T-cell (CD103 + ) frequency in early-stage NSCLC correlated with improved prognosis, putatively due to their greater capacity to produce IFNc than other TIL subsets. 26,27 Accordingly, current immunotherapy strategies are focused on increasing the induction of tumorspecific effector CD8 + T cells, namely immune checkpoint blockade therapy (ICPB), ACT and antitumor vaccination. 5 Other leucocytes associated with tumorderived immunosuppression Lung tumor cells promote an immunosuppressive TME through production of cytokines, including IL-10, vascular endothelial growth factor and TGFb.…”

Section: Cytotoxic T Lymphocytesmentioning

confidence: 99%

The role and therapeutic implications of T cells in cancer of the lung

2019

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Lung cancer remains the leading cause of cancer‐related death worldwide. The disease is classified into two major subtypes, small‐cell lung cancer (SCLC) and the more prevalent non‐small‐cell lung cancer (NSCLC). First‐line conventional therapies, such as chemotherapy, radiotherapy and surgery, have offered limited benefit, and patient prognosis remains poor with post‐treatment recurrences representing a major cause of morbidity. Consequently, there is an urgent need for improved therapeutic options. Historically, NSCLC has been considered a non‐immunogenic disease. However, increased understanding of tumor‐immune interactions has challenged this paradigm in both lung and other malignancies, with cancer elimination by tumor‐specific T cells increasingly well described in a myriad of solid tumors. Recent evidence has demonstrated that absent or weak anticancer responses are likely a product of tumor‐derived immunosuppression. This knowledge, along with a greater appreciation for the role of T cells in lung cancer elimination, has driven development of novel immunotherapeutic approaches which are demonstrating remarkable clinical efficacy. This review examines the role of T cells in lung cancer, discussing the direction and clinical significance of current and future immunotherapeutic strategies.

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“…Integrin αEβ7 (CD103), the ligand to E-cadherin, is also used to characterize T RM but CD103 expression is mostly confined to CD8+ T RM and a minor subset of CD4+T RM [3][4][5][6]. Recent studies have characterized CD4+ T RM subsets in multiple organs including lungs, liver, skin, intestines, vagina and lymphoid sites where they provide protective responses and direct the recruitment of immune cells [7][8][9][10]. In the human intestine, the majority of CD4+T RM are CD69+CD103− and a minority are CD69+CD103+ [3] but little information is available concerning their role in oral immunization or enteric infections.…”

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confidence: 99%

Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4+ T cells in the human terminal ileum lamina propria and epithelial compartments

et al. 2020

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Background: Salmonella enterica serovar Typhi (S. Typhi) is a highly invasive bacterium that infects the human intestinal mucosa and causes ~ 11.9-20.6 million infections and ~ 130,000-223,000 deaths annually worldwide. Oral typhoid vaccine Ty21a confers a moderate level of long-lived protection (5-7 years) in the field. New and improved vaccines against enteric pathogens are needed but their development is hindered by a lack of the immunological correlates of protection especially at the site of infection. Tissue resident memory T (T RM ) cells provide immediate adaptive effector immune responsiveness at the infection site. However, the mechanism(s) by which S. Typhi induces T RM in the intestinal mucosa are unknown. Here, we focus on the induction of S. Typhi-specific CD4+T RM subsets by Ty21a in the human terminal ileum lamina propria and epithelial compartments. Methods:Terminal ileum biopsies were obtained from consenting volunteers undergoing routine colonoscopy who were either immunized orally with 4 doses of Ty21a or not. Isolated lamina propria mononuclear cells (LPMC) and intraepithelial lymphocytes (IEL) CD4+T RM immune responses were determined using either S. Typhi-infected or noninfected autologous EBV-B cell lines as stimulator cells. T-CMI was assessed by the production of 4 cytokines [interferon (IFN)γ, interleukin (IL)-2, IL-17A and tumor necrosis factor (TNF)α] in 36 volunteers (18 vaccinees and 18 controls volunteers). Results:Although the frequencies of LPMC CD103+ CD4+T RM were significant decreased, both CD103+ and CD103− CD4+T RM subsets spontaneously produced significantly higher levels of cytokines (IFNγ and IL-17A) following Ty21a-immunization. Importantly, we observed significant increases in S. Typhi-specific LPMC CD103+ CD4+T RM (IFNγ and IL-17A) and CD103− CD4+T RM (IL-2 and IL-17A) responses following Ty21a-immunization. Further, differences in S. Typhi-specific responses between these two CD4+T RM subsets were observed following multifunctional analysis. In addition, we determined the effect of Ty21a-immunization on IEL and observed significant changes in the frequencies of IEL CD103+ (decrease) and CD103− CD4+T RM (increase) following immunization. Finally, we observed that IEL CD103− CD4+T RM , but not CD103+ CD4+T RM , produced increased cytokines (IFNγ, TNFα and IL-17A) to S. Typhi-specific stimulation following Ty21a-immunization. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' Conclusions: Oral Ty21a-immunization elicits distinct compartment sp...

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Functional Heterogeneity of CD4+ Tumor-Infiltrating Lymphocytes With a Resident Memory Phenotype in NSCLC

Cited by 99 publications

References 69 publications

Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

Redefining CD4 T cell residency: Helper T cells orchestrate protective humoral immunity in the lung

The role and therapeutic implications of T cells in cancer of the lung

Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4+ T cells in the human terminal ileum lamina propria and epithelial compartments

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