SP5.1.11 The immune landscape of the Tumour draining lymph node and the Tumour Microenvironment in oesophageal; A novel therapeutic target

Abstract Aim The tumour microenvironment (TME) and tumour-draining lymph node microenvironment (LNME) remain poorly understood. Our study profiles the immune, angiogenic and inflammatory environment of the LNME and the TME of oesophagogastric patients. Methods The prognositc value of nodal status, clinical stage and tumour regression grade (TRG) was evaluated using a cohort of OAC patients (n = 702). Immune checkpoints (ICs) on tumour-draining lymph nodes(TDLNs, n = 6) and tumour tissue(n = 9) at surgical resection was assessed by flow cytometry. We also screened for cytokines, angiogenic mediators and chemokines. Using The Cancer Genome Atlas (TCGA), protein and mRNA levels (n = 72) and mutated versus non-mutated copies(n = 87) of this panel was correlated with survival. Results The frequency of CD3+TIM-3 and PD-1+T cells in TDLNs positively correlated with clinical tumour status as did CD8 + PD-1+TIGIT + T cells with nodal burden. Pro-angiogenic factor bFGF was significantly higher within the TME compared with the LNME. PIGF and SAA mediators of tumour growth were significantly higher in the LNME and levels of SAA in LNME positively correlated with adverse features. High levels of pro inflammatory IL-8,IL-6 and Flt1, mutations in pro-inflammatory genes CCL26,IL-31 and IL-17C and anti-tumour IL-1RN and CCL22 correlated with reduced overall survival. Conclusions The TME is more immunosuppressive than the TDLN, however, certain pro-angiogenic factors were enriched in TDLNs suggesting the priming of a pre-metastatic niche. Given the association of ICs with clinical features and tumour biology this may help to inform novel therapeutic approaches.

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The Prognostic Value of the Lymph Node in Oesophageal Adenocarcinoma; Incorporating Clinicopathological and Immunological Profiling

Cancers ◽

10.3390/cancers13164005 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4005

Author(s):

Noel E. Donlon ◽

Maria Davern ◽

Andrew Sheppard ◽

Robert Power ◽

Fiona O’Connell ◽

...

Keyword(s):

Lymph Node ◽

Prognostic Value ◽

Response Rates ◽

Tumour Microenvironment ◽

Oesophageal Adenocarcinoma ◽

Standards Of Care ◽

Immune Checkpoints ◽

Tumour Regression ◽

Tumour Regression Grade ◽

Radio Therapy

Response rates to the current gold standards of care for treating oesophageal adenocarcinoma (OAC) remain modest with 15–25% of patients achieving meaningful pathological responses, highlighting the need for novel therapeutic strategies. This study consists of immune, angiogenic, and inflammatory profiling of the tumour microenvironment (TME) and lymph node microenvironment (LNME) in OAC. The prognostic value of nodal involvement and clinicopathological features was compared using a retrospective cohort of OAC patients (n = 702). The expression of inhibitory immune checkpoints by T cells infiltrating tumour-draining lymph nodes (TDLNs) and tumour tissue post-chemo(radio)therapy at surgical resection was assessed by flow cytometry. Nodal metastases is of equal prognostic importance to clinical tumour stage and tumour regression grade (TRG) in OAC. The TME exhibited a greater immuno-suppressive phenotype than the LNME. Our data suggests that blockade of these checkpoints may have a therapeutic rationale for boosting response rates in OAC.

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The race for the prize: T-cell trafficking strategies for optimal surveillance

Blood ◽

10.1182/blood-2012-04-424655 ◽

2012 ◽

Vol 120 (7) ◽

pp. 1432-1438 ◽

Cited By ~ 23

Author(s):

Minyi Lee ◽

Judith N. Mandl ◽

Ronald N. Germain ◽

Andrew J. Yates

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Optimization Problem ◽

Cell Trafficking ◽

T Cell Trafficking ◽

Cell Responses ◽

Major Histocompatibility Complexes ◽

Draining Lymph Node ◽

Slow Transit

Abstract The initiation of T-cell responses requires rare precursors to locate a draining lymph node (dLN) and encounter dendritic cells (DCs) presenting peptide-major histocompatibility complexes (pMHCs). To locate this needle in the haystack rapidly, T cells face an optimization problem—what is the most efficient trafficking strategy for surveillance and recirculation through blood? Two extremes are scanning low numbers of DCs per node with frequent recirculation, or meticulous surveillance with infrequent recirculation. Naive T cells also require stimulation by self-pMHCs. To enable efficient location of both foreign and self, has evolution settled on an optimum time for T cells to spend surveying each lymph node? Using a data-driven mathematical model, we show the most efficient strategy for detecting antigen in a dLN depends on its abundance. Detection of low-density antigen is optimized with systemically slow transit. In contrast, at high densities or if dLN egress is restricted, rapid transit through other nodes is optimal. We argue that blood-lymph recirculation dynamics facilitate a trade-off, and are consistent with dominant roles for the very early detection of rare foreign antigens in a dLN, and the efficient accumulation of signals from systemically distributed self-antigens.

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Abstract 526: Tumor-draining lymph node irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the abscopal effect

10.1158/1538-7445.sabcs18-526 ◽

2019 ◽

Author(s):

Zachary S. Buchwald ◽

Tahseen H. Nasti ◽

Christiane S. Eberhardt ◽

Andreas Wieland ◽

David Lawson ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Cd8 T Cells ◽

Abscopal Effect ◽

Draining Lymph Node ◽

Tumor Draining Lymph Node ◽

Lymph Node Irradiation

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Combined Treatment with Short Synthetic Anti-Lymphoma Peptide and CpG ODN; A Therapeutic Vaccine Which cures the A20 Lymphoma in Balb/C Mice.

Blood ◽

10.1182/blood.v112.11.1586.1586 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1586-1586

Author(s):

Arne Kolstad ◽

Roch Houot ◽

Gerd Berge ◽

Øystein Rekdal ◽

Debra Czerwinski ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Combined Treatment ◽

Therapeutic Vaccine ◽

Immunological Memory ◽

Separate Experiment ◽

Lymphoma Cells ◽

Draining Lymph Node ◽

Ifn Γ

Abstract Background. The short synthetic peptide 302 has been shown to induce rapid membrane disruption of lymphoma cells in vitro and necrosis of local tumors in the A20 lymphoma model in Balb/c mice. In order to stimulate the immune system to generate an anti-tumor response we designed a model where intra-tumor injections of peptide 302 was combined with sc injections of the Toll-like receptor 9 binding synthetic oligonucleotide CpG 1826. Methods. Balb/c mice were inoculated with A20 lymphoma cells sub-cutaneously (s.c.) on the abdomen. When the tumors reached a size of 5–7 mm, 302 peptide was administered directly into the tumors on days 1 and 6. CpG 1826 was injected s.c. on days 1–4 and 6–8. Tumor growth was measured repeatedly during follow-up. A20-specific T-cell responses were detected by culturing peripheral blood lymphocytes from treated animals for 24 hours with A20 lymphoma cells and analyzing for intracellular IFN-γ production by flow cytometry. To dissect the role of T-cell subtypes, the treatment was performed in animals depleted for CD4 or CD8 positive T-cells. In order to show A20 specific immunological memory, cured animals were re-challenged with the A20 lymphoma or the carcinoma cell line CT26. Results. Combined treatment with peptide 302 and CpG 1826 cured 8 out of 10 mice, compared to only 2 out of 10 mice who received peptide 302 alone or CpG 1826 alone. Cured mice were followed for 9 weeks without relapsing. Similar results with the combination of peptide 302 and CpG were observed in a separate experiment. The highest cure rate was achieved when injecting CpG 1826 s.c. in the tumors draining lymph node area as compared to administration of CPG 1826 in a non-draining lymph node region or intra-peritoneal. Animals treated with peptide 302 + CpG 1826 or CpG 1826 alone developed CD8-specific IFN-γ responses against A20 cells. In one separate experiment CD8 knock-out mice did not respond to the treatment, unlike animals depleted for CD4+ cells and normal mice. Only 1 out of 10 cured animals re-challenged with the A20 lymphoma developed a new tumor, a result that was reproduced in a second experiment. Conclusion: Treatment with intra-tumor injections of the anti-lymphoma peptide 302 in combination with CpG 1826 s.c. in the draining lymph node region cured established A20 tumors, induced tumor-specific CD8 positive tumor-reactive T-cells, and induced specific immunological memory. This principle represents a novel therapeutic vaccine approach.

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Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells.

Journal of Experimental Medicine ◽

10.1084/jem.157.5.1448 ◽

1983 ◽

Vol 157 (5) ◽

pp. 1448-1460 ◽

Cited By ~ 69

Author(s):

C D Mills ◽

R J North

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Cell Response ◽

Passive Transfer ◽

T Cell Response ◽

Suppressor T Cells ◽

Tumor Bearing ◽

Draining Lymph Node ◽

Adoptive Immunity

The results of this study with the P815 mastocytoma confirm the results of previous studies that showed that the passive transfer of tumor-sensitized T cells from immunized donors can cause the regression of tumors growing in T cell-deficient (TXB) recipients, but not in normal recipients. The key additional finding was that the expression of adoptive immunity against tumors growing in TXB recipients is immediately preceded by a substantial production of cytolytic T cells in the recipients' draining lymph node. On the other hand, failure of adoptive immunity to be expressed against tumors growing in normal recipients was associated with a cytolytic T cell response of much lower magnitude, and a similar low magnitude response was generated in TXB recipients infused with normal spleen cells and in tumor-bearing control mice. Because the passively transferred sensitized T cells possessed no cytolytic activity of their own, the results indicate that the 6-8-d delay before adoptive immunity is expressed represents the time needed for passively transferred helper or memory T cells to give rise to a cytolytic T cell response of sufficient magnitude to destroy the recipient's tumor. In support of this interpretation was the additional finding that inhibition of the expression of adoptive immunity by the passive transfer of suppressor T cells from tumor-bearing donors was associated with a substantially reduced cytolytic T cell response in the recipient's draining lymph node. The results serve to illustrate that interpretation of the results of adoptive immunization experiments requires a knowledge of the events that take place in the adoptively immunized recipient. They support the interpretation that suppressor T cells function in this model to "down-regulate" the production of cytolytic effector T cells.

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