scholarly journals Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts

2020 ◽  
Author(s):  
Dimitra Kerdidani ◽  
Emmanouil Aerakis ◽  
Kleio-Maria Verrou ◽  
Petros Stamoulis ◽  
Katerina Goudevenou ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Human Lung ◽  
Alveolar Type ◽  
Cancer Associated Fibroblasts ◽  
Antigen Presenting ◽  
Draining Lymph Nodes

ABSTRACTA key unknown of the functional space in tumor immunity is whether physiologically relevant cancer antigen presentation occurs solely in draining lymph nodes versus tumors. Professional antigen presenting cells, i.e. the dendritic cells, are scarce and immature within tumors, greatly outnumbered by MHCII expressing non-hematopoietic cells, such as antigen-presenting cancer-associated fibroblasts (apCAFs). We hypothesized that after their exit from tumor-draining lymph nodes T cells depend on a second wave of antigen presentation provided in situ by structural cells. We show that dense apCAF regions in human lung tumors define hot immunological spots with increased numbers of CD4 T cells. The transcriptomic profile of human lung apCAFs aligned to that of pancreatic apCAFs across mice and humans and were both enriched for alveolar type II genes, suggesting an epithelial origin. Mechanistically, human apCAFs directly activated the TCRs of adjacent effector CD4 T cells and at the same time produced high levels of c1q, which acted on surface c1qbp on T cells to rescue them from apoptosis. Fibroblast-specific deletion of MHCII in mice impaired local MHCII immunity and accelerated tumor growth, while inducing c1qbp overexpression in adoptively transferred T cells expanded their numbers within tumors and reduced tumour burden. Collectively, our work shows that tumor T cell immunity post lymph node exit requires peripheral antigen presentation by a subset of CAFs and proposes a new conceptual framework upon which effective cancer immunotherapies can be built.

scholarly journals Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts.

2021 ◽  
Author(s):  
Dimitra Kerdidani ◽  
Emmanouil Aerakis ◽  
Kleio Verrou ◽  
Petros Stamoulis ◽  
Katerina Goudevenou ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Human Lung ◽  
Alveolar Type ◽  
Cancer Associated Fibroblasts ◽  
Antigen Presenting ◽  
Draining Lymph Nodes

Abstract A key unknown of the functional space in tumor immunity is whether physiologically relevant cancer antigen presentation occurs solely in draining lymph nodes versus tumors. Professional antigen presenting cells, i.e. the dendritic cells, are scarce and immature within tumors, greatly outnumbered by MHCII expressing non-hematopoietic cells, such as antigen-presenting cancer-associated fibroblasts (apCAFs). We hypothesized that after their exit from tumor-draining lymph nodes T cells depend on a second wave of antigen presentation provided in situ by structural cells. We show that dense apCAF regions in human lung tumors define hot immunological spots with increased numbers of CD4 T cells. The transcriptomic profile of human lung apCAFs aligned to that of pancreatic apCAFs across mice and humans and were both enriched for alveolar type II genes, suggesting an epithelial origin. Mechanistically, human apCAFs directly activated the TCRs of adjacent effector CD4 T cells and at the same time produced high levels of c1q, which acted on surface c1qbp on T cells to rescue them from apoptosis. Fibroblast-specific deletion of MHCII in mice impaired local MHCII immunity and accelerated tumor growth, while inducing c1qbp overexpression in adoptively transferred T cells expanded their numbers within tumors and reduced tumour burden. Collectively, our work shows that tumor T cell immunity post lymph node exit requires peripheral antigen presentation by a subset of CAFs and proposes a new conceptual framework upon which effective cancer immunotherapies can be built.

Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts

2022 ◽  
Vol 219 (2) ◽  
Author(s):  
Dimitra Kerdidani ◽  
Emmanouil Aerakis ◽  
Kleio-Maria Verrou ◽  
Ilias Angelidis ◽  
Katerina Douka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Lung Tumor ◽  
Functional Space ◽  
Pancreatic Tumors ◽  
Cell Immunity ◽  
Antigen Presenting

A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation.

scholarly journals Human CD4+T Cells Present Within the Microenvironment of Human Lung Tumors Are Mobilized by the Local and Sustained Release of IL-12 to Kill Tumors In Situ by Indirect Effects of IFN-γ

2003 ◽  
Vol 170 (1) ◽  
pp. 400-412 ◽  
Author(s):  
Stephen D. Hess ◽  
Nejat K. Egilmez ◽  
Nicola Bailey ◽  
Timothy M. Anderson ◽  
Edith Mathiowitz ◽  
...  
Keyword(s):  
T Cells ◽  
Sustained Release ◽  
Indirect Effects ◽  
Cd4 T Cells ◽  
Human Lung ◽  
Lung Tumors ◽  
Ifn Γ

Cellular infiltration at skin lesions and draining lymph nodes of sheep infested with adultHyalomma anatolicum anatolicumticks

Parasitology ◽  
2005 ◽  
Vol 131 (5) ◽  
pp. 657-667 ◽  
Author(s):  
D. K. V. BOPPANA ◽  
S. K. WIKEL ◽  
D. G. RAJ ◽  
M. B. MANOHAR ◽  
J. LALITHA
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Antigen Presenting Cells ◽  
Skin Lesions ◽  
Cellular Infiltration ◽  
Regional Lymph Nodes ◽  
Mhc Ii ◽  
Skin Biopsies ◽  
Antigen Presenting ◽  
Draining Lymph Nodes

Immunohistochemical analysis of skin and draining lymph nodes of sheep repeatedly infested with the ixodid tickHyalomma anatolicum anatolicumwere studied for different antigen-presenting cells and lymphocyte subpopulations. Infiltration of neutrophils, macrophages and lymphocytes adjacent to the tick bite site were observed. Skin biopsies showed significant increases in dermal infiltration of CD8+and γδ+T cells at 72 h and 8 days after both primary and secondary infestation. Infiltrations of MHC-II DR/DQ decreased at 72 h after tick infestation, whereas significant increases were recorded for 8-day skin biopsies. CD1+cellular infiltrations were observed during secondary infestations at the dermis. Decreased ratios of CD4[ratio ]CD8 T cells and MHC-II[ratio ]CD1 antigen-presenting cells were observed in both infestations compared to healthy skin biopsies. Ratios of αβ[ratio ]γδ T cells increased gradually during infestation compared to uninfested skin. The regional lymph nodes from tick-infested sheep showed an increased CD8+, γδ+T and CD1+cellular infiltration compared to control lymph nodes. CD4+T cells were decreased. There were no significant changes in CD45R+cellular infiltration either at skin lesions or regional lymph nodes.

scholarly journals CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central–memory cells

2006 ◽  
Vol 203 (4) ◽  
pp. 1045-1054 ◽  
Author(s):  
Drew M. Catron ◽  
Lori K. Rusch ◽  
Jason Hataye ◽  
Andrea A. Itano ◽  
Marc K. Jenkins
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd4 T Cells ◽  
Primary Response ◽  
Central Memory ◽  
Secondary Response ◽  
Memory Cells ◽  
Mhc Ii ◽  
Central Memory Cells ◽  
Draining Lymph Nodes

We explored the relationship between the time of naive CD4+ T cell exposure to antigen in the primary immune response and the quality of the memory cells produced. Naive CD4+ T cells that migrated into the skin-draining lymph nodes after subcutaneous antigen injection accounted for about half of the antigen-specific population present at the peak of clonal expansion. These late-arriving T cells divided less and more retained the central–memory marker CD62L than the T cells that resided in the draining lymph nodes at the time of antigen injection. The fewer cell divisions were related to competition with resident T cells that expanded earlier in the response and a reduction in the number of dendritic cells displaying peptide–major histocompatibility complex (MHC) II complexes at later times after antigen injection. The progeny of late-arriving T cells possessed the phenotype of central–memory cells, and proliferated more extensively during the secondary response than the progeny of the resident T cells. The results suggest that late arrival into lymph nodes and exposure to antigen-presenting cells displaying lower numbers of peptide–MHC II complexes in the presence of competing T cells ensures that some antigen-specific CD4+ T cells divide less in the primary response and become central–memory cells.

scholarly journals MHC Class II Expression Restricted to CD8α+ and CD11b+ Dendritic Cells Is Sufficient for Control of Leishmania major

2004 ◽  
Vol 199 (5) ◽  
pp. 725-730 ◽  
Author(s):  
Maria P. Lemos ◽  
Fatima Esquivel ◽  
Phillip Scott ◽  
Terri M. Laufer
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Cd4 T Cell ◽  
Major Infection ◽  
Mhc Ii ◽  
Antigen Presenting

Control of the intracellular protozoan, Leishmania major, requires major histocompatibility complex class II (MHC II)–dependent antigen presentation and CD4+ T cell T helper cell 1 (Th1) differentiation. MHC II–positive macrophages are a primary target of infection and a crucial effector cell controlling parasite growth, yet their function as antigen-presenting cells remains controversial. Similarly, infected Langerhans cells (LCs) can prime interferon (IFN)γ–producing Th1 CD4+ T cells, but whether they are required for Th1 responses is unknown. We explored the antigen-presenting cell requirement during primary L. major infection using a mouse model in which MHC II, I-Aβb, expression is restricted to CD11b+ and CD8α+ dendritic cells (DCs). Importantly, B cells, macrophages, and LCs are all MHC II–negative in these mice. We demonstrate that antigen presentation by these DC subsets is sufficient to control a subcutaneous L. major infection. CD4+ T cells undergo complete Th1 differentiation with parasite-specific secretion of IFNγ. Macrophages produce inducible nitric oxide synthase, accumulate at infected sites, and control parasite numbers in the absence of MHC II expression. Therefore, CD11b+ and CD8α+ DCs are not only key initiators of the primary response but also provide all the necessary cognate interactions for CD4+ T cell Th1 effectors to control this protozoan infection.

scholarly journals Tumor ablation plus co-administration of CpG and saponin adjuvants affects IL-1 production and multifunctional T cell numbers in tumor draining lymph nodes

2020 ◽  
Vol 8 (1) ◽  
pp. e000649
Author(s):  
Tonke K Raaijmakers ◽  
Renske J E van den Bijgaart ◽  
Martijn H den Brok ◽  
Melissa Wassink ◽  
Annemarie de Graaf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Tumor Ablation ◽  
Polymorphonuclear Neutrophil ◽  
Cell Numbers ◽  
Draining Lymph Nodes

BackgroundTumor ablation techniques, like cryoablation, are successfully used in the clinic to treat tumors. The tumor debris remaining in situ after ablation is a major antigen depot, including neoantigens, which are presented by dendritic cells (DCs) in the draining lymph nodes to induce tumor-specific CD8+T cells. We have previously shown that co-administration of adjuvants is essential to evoke strong in vivo antitumor immunity and the induction of long-term memory. However, which adjuvants most effectively combine with in situ tumor ablation remains unclear.Methods and resultsHere, we show that simultaneous administration of cytidyl guanosyl (CpG) with saponin-based adjuvants following cryoablation affects multifunctional T-cell numbers and interleukin (IL)-1 induced polymorphonuclear neutrophil recruitment in the tumor draining lymph nodes, relative to either adjuvant alone. The combination of CpG and saponin-based adjuvants induces potent DC maturation (mainly CpG-mediated), antigen cross-presentation (mainly saponin-based adjuvant mediated), while excretion of IL-1β by DCs in vitro depends on the presence of both adjuvants. Most strikingly, CpG/saponin-based adjuvant exposed DCs potentiate antigen-specific T-cell proliferation resulting in multipotent T cells with increased capacity to produce interferon (IFN)γ, IL-2 and tumor necrosis factor-α in vitro. Also in vivo the CpG/saponin-based adjuvant combination plus cryoablation increased the numbers of tumor-specific CD8+T cells showing enhanced IFNγ production as compared with single adjuvant treatments.ConclusionsCollectively, these data indicate that co-injection of CpG with saponin-based adjuvants after cryoablation induces an increased amount of tumor-specific multifunctional T cells. The combination of saponin-based adjuvants with toll-like receptor 9 adjuvant CpG in a cryoablative setting therefore represents a promising in situ vaccination strategy.

Sign in / Sign up

Export Citation Format

Share Document