scholarly journals ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5021
Author(s):  
Dechen Wangmo ◽  
Prem K. Premsrirut ◽  
Ce Yuan ◽  
William S. Morris ◽  
Xianda Zhao ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Lymph Nodes ◽  
Mismatch Repair ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
T Cell Priming ◽  
Draining Lymph Nodes

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregulation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.

scholarly journals Loss of ACKR4 in tumor cells dysregulates dendritic cell migration to tumor-draining lymph nodes and T-cell priming

2021 ◽  
Author(s):  
Dechen Wangmo ◽  
Prem K. Premsrirut ◽  
Ce Yuan ◽  
William S. Morris ◽  
Xianda Zhao ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Lymph Nodes ◽  
Mismatch Repair ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
New Findings ◽  
T Cell Priming ◽  
Draining Lymph Nodes

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but failed in the mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is known for regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and immunoregulation are unclear. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockades. Finally, we identified that microRNA-552 negatively regulates ACKR4 expression in human CRC. Taken together, our work identifies a critical mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC tumors.

scholarly journals Chemotherapy but not the tumor draining lymph nodes determine the immunotherapy response in secondary tumors

2019 ◽  
Author(s):  
Xianda Zhao ◽  
Beminet Kassaye ◽  
Dechen Wangmo ◽  
Emil Lou ◽  
Subbaya Subramanian
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Cytotoxic Chemotherapy ◽  
Checkpoint Blockade ◽  
Secondary Tumors ◽  
Sequential Administration ◽  
Cytotoxic Treatment ◽  
Draining Lymph Nodes

SUMMARYImmunotherapies are used as adjuvant therapies for cancers. However, knowledge of how traditional cancer treatments affect immunotherapies is limited. Using mouse models, we demonstrate that tumor-draining lymph nodes (TdLNs) are critical for tumor antigen-specific T-cell response. However, removing TdLNs concurrently with established primary tumors did not affect the immune checkpoint blockade (ICB) response on localized secondary tumor due to immunotolerance in TdLNs and distribution of antigen-specific T cells in peripheral lymphatic organs. Notably, treatment response improved with sequential administration of 5-fluorouracil (5-FU) and ICB compared to concurrent administration of ICB with 5-FU. Immune profiling revealed that using 5-FU as induction treatment increased tumor visibility to immune cells, decreased immunosuppressive cells in the tumor microenvironment, and limited chemotherapy-induced T-cell depletion. We show that the effect of traditional cytotoxic treatment, not TdLNs, influences immunotherapy response in localized secondary tumors. We postulate essential considerations for successful immunotherapy strategies in clinical conditions.Graphic abstractThe effects of tumor-draining lymph nodes (TdLNs) resection and a combination of cytotoxic chemotherapy on immune checkpoint blockade therapies are evaluated in this study. TdLNs resection was adverse in eliciting an antitumor immune response in early-stage tumors, but not in late-stage tumors. Further, sequential treatments with cytotoxic chemotherapy and immunotherapy showed better tumor control compared to concurrent combinatorial treatments.

SOX2 as a target for immunotherapy of pediatric gliomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22012-e22012 ◽  
Author(s):  
Juan Vasquez ◽  
Anita Huttner ◽  
Lin Zhang ◽  
Asher Marks ◽  
Amy Chan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Cell Mass ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Low Grade ◽  
Glial Tumors

e22012 Background: New treatments are needed to improve outcomes for pediatric gliomas. Immune checkpoint inhibitors are effective therapies in tumors with a high mutation burden that express multiple neo-antigens. However, for pediatric tumors that carry few mutations, there is a need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors, and the capacity of the immune system in these patients to recognize SOX2, has not been studied. Methods: We examined the expression of SOX2 on paraffin-embedded tissue from pediatric glial tumors (n = 30). The presence of T cell immunity to SOX2 was examined in both blood and tumor-infiltrating T cells using antigen-dependent cytokine and T cell proliferation assays (n = 15). The nature of tumor-infiltrating immune cells in glial tumors (n = 4) was analyzed using single cell mass cytometry. Results: SOX2 is expressed by tumor cells but not surrounding normal tissue in all low grade gliomas (n = 15), high grade gliomas (n = 7), ependymomas (n = 3) and in 60% of oligodendrogliomas (n = 5). T cells against SOX2 can be detected in blood and tumor tissue in 33% of patients. CD4 and CD8 tumor infiltrating T-cells display a higher proportion of PD-1 expression compared to circulating T cells (p < 0.05). Glial CD4 and CD8 T cells are enriched for tissue resident memory phenotype (TRM; CD45RO+, CD69+, CCR7-) and the expression of PD-1 is primarily on these TRM cells (p < 0.05). A subset of CD4 and CD8 TRM cells also co-express multiple inhibitory checkpoints including PD-L1 and TIGIT. Glial tumors also contain NK cells with reduced expression of lytic granzyme (p < 0.05). Conclusions: Our data demonstrate in vivo immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Our data also suggest that the TRM subset of tumor-infiltrating T cells may be key targets for immune checkpoint blockade, and harnessing tumor immunity will likely require the combined targeting of multiple inhibitory checkpoints. Future efforts to target SOX2 with dendritic cell vaccines combined with immune checkpoint blockade could provide effective tumor immunity and improve outcomes in pediatric brain tumors.

scholarly journals Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

2021 ◽  
Vol 118 (45) ◽  
pp. e2105323118
Author(s):  
William W. Ho ◽  
Igor L. Gomes-Santos ◽  
Shuichi Aoki ◽  
Meenal Datta ◽  
Kosuke Kawaguchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Liver Metastasis ◽  
Liver Metastases ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

scholarly journals Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4616
Author(s):  
Yasuhiro Kanda ◽  
Taku Okazaki ◽  
Tomoya Katakai
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Cell Motility ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumor Immunotherapy ◽  
Checkpoint Blockade ◽  
Draining Lymph Nodes

The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.

scholarly journals 564 Single-cell transcriptomic analysis of immune compartments following combination immunotherapy treatment in poorly immunogenic tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A593-A593
Author(s):  
Ang Cui ◽  
Kelly Moynihan ◽  
Shuqiang Li ◽  
Chensu Wang ◽  
Jackson Southard ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lymph Nodes ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
List Type ◽  
Combination Immunotherapy ◽  
Effective Response ◽  
Draining Lymph Nodes

BackgroundA major goal in cancer immunology is to rationally design combination therapies that lead to a higher response rate, especially for poorly immunogenic tumors that do not respond to immune checkpoint blockade therapy alone. We previously developed a combination therapeutic strategy, termed AIPV, consisting of a tumor-targeting antibody, a recombinant interleukin-2 with an extended half-life, an anti-PD-1 antibody, and a T cell vaccine [1]. The full AIPV therapy can eradicate large, aggressive, poorly immunogenic tumors in multiple mouse tumor models. However, the exact cellular and molecular pathways involved in such an effective response remain poorly understood.MethodsIn this study, we used single-cell RNA-sequencing to define the detailed cellular and molecular changes in tumors and tumor-draining lymph nodes following the full AIPV therapy or a less effective sub-combination therapy in mice with poorly immunogenic B16F10 tumors.ResultsUsing our approach, we were able to uncover T cells, NK cells, neutrophils, macrophages/monocytes, classical dendritic cells, and plasmacytoid dendritic cells in tumors. We observed profound remodeling of every immune cell type following the effective therapeutic treatment. In particular, we found that classical dendritic cells take up tumor antigens, become activated, and migrate to draining lymph nodes following the AIPV therapy, but not following the less effective IPV therapy. We characterized the transcriptomic changes of these dendritic cells and found that they over-express molecules involved in antigen uptake.ConclusionsOur study comprehensively characterized a system that can overcome resistance to immune checkpoint blockade therapy, paving a cellular and molecular roadmap for immune-based therapeutic strategies that offer clinical benefits for poorly immunogenic tumors.ReferencesMoynihan KD, Opel CF, Szeto GL, Tzeng A, Zhu EF, Engreitz JM, et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat Med. 2016;22: 1402–1410.Ethics ApprovalAll mouse experiments were reviewed and approved by the Koch Institute and Broad Institute Animal Care and Use Committee (IACUC) (ID 0222-08-18).

scholarly journals Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

Sign in / Sign up

Export Citation Format

Share Document