CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells

Bunse, Mario; Pfeilschifter, Janina Marie; Bluhm, Julia; Zschummel, Maria; Joedicke, Jara J.; Wirges, Anthea; Stark, Helen; Kretschmer, Vivien; Chmielewski, Markus; Uckert, Wolfgang; Abken, Hinrich; Westermann, Jörg; Rehm, Armin; Höpken, Uta E.

doi:10.1038/s41467-020-20488-3

Cited by 36 publications

(28 citation statements)

References 65 publications

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“…The evidence of CD4 + CXCL13 + T cells shaping TME composition may represent a LR-CHL–specific mechanism of immune dysfunction, suggesting that therapeutic targeting of these cells might reverse their immunosuppressive effects ( 44 ). Interestingly, therapeutic agents targeting CXCL13/CXCR5 are currently being explored in the context of autoimmune disease and non-Hodgkin lymphoma ( 40 , 45 ). The characteristics of CD4 + CXCL13 + T cells in LR-CHL are very similar to a CXCL13-producing TFH population that lacks CXCR5 expression identified in breast cancer ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma

Aoki

Chong

Takata

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4+ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1+CXCL13+ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5+ normal B cells in close proximity to CXCL13+ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1+CXCL13+ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1+CXCL13+ T cells as a treatment target in LR-CHL.

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Section: Discussionmentioning

confidence: 99%

Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma

Aoki

Chong

Takata

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…It is not only improved homing to the tumor tissue but also attacking the tumor stroma that augments anti-tumor efficacy. As a result of these analyses, the concept is drawn that successful eradication of advanced tumors requires CAR T cells that target the stroma in addition to targeting the specific cancer cells 190,191 .…”

Section: Towards Environment Sensing Car T Cellsmentioning

confidence: 99%

Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors

Abken

2021

Human Gene Therapy

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Advancement in our understanding of immune cell recognition and emerging cellular engineering technologies during the last decades made active manipulation of the T cell response possible. Synthetic immunology is providing us with an expanding set of composite receptor molecules capable to reprogram immune cell function in a predefined fashion. Since the first prototypes in the late 1980s, the design of chimeric antigen receptors (CARs; T-bodies, immunoreceptors), has followed a clear line of stepwise improvements from antigen-redirected targeting to designed “living factories” delivering transgenic products on demand. Building on basic research and creative clinical exploration, CAR T cell therapy has been achieving spectacular success in the treatment of hematologic malignancies, now beginning to improve the outcome of cancer patients. In this study, we briefly review the history of CARs and outline how the progress in the basic understanding of T cell recognition and of cell engineering technologies made novel therapies possible.

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“…Chimeric antigen receptor (CAR)-T cells have demonstrated to be effective against R/R FL [67,68], tFL [69,70], and diffuse large B-cell lymphoma [68][69][70]. To further target Tfh cells and B-cell lymphoma cells, CAR-T cells targeting CXCR5 have been recently designed with demonstrated comparable activity with conventional CD19 CAR-T cells [71]. However, CXCR5 + CD8 + T cells are present in human tonsils and FL and exhibited strong cytotoxic activity, although the mean fluorescent intensity of CXCR5 in CD8 + T cells was much lower than B cells and CD4 + T cells in human tonsils and FL specimens [72].…”

Section: Follicular Helper T Cellsmentioning

confidence: 99%

“…Therefore, there is a possibility that the CXCR5 CAR-T might cause fractricide of efficient cytotoxic T cells. This may explain CXCR5 CAR show similar antitumor activity to CD19 CAR, although they used mantle cell lymphoma cells not FL cells implanted in NOD/Scid/IL2Rγnull mice [71].…”

Section: Follicular Helper T Cellsmentioning

confidence: 99%

The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential

Watanabe

2021

IJMS

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In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal fistromal cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.

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CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells

Cited by 36 publications

References 65 publications

Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma

Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma

Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors

The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential

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