TABLE 1.
Summarising the studies investigating the importance of TDLN in anti-tumour immunity following immunotherapy.
| Pre-clinical studies | Study | Model | Conclusions |
|---|---|---|---|
| Evidence of Antigen presentation in TDLN | Chamoto et al. (2006) | Th-1 cell therapy in an OVA-expressing tumour murine model. | APC travel to TDLN presenting tumour antigen, resulting in tumour specific Th1 cell proliferation, immune infiltration and tumour regression. |
| Marzo et al. (1999) | HA specific CD8+ T cell adoptive transfer in a murine HA-expressing tumour model. | Tumour antigen stimulates expansion of T cells in TDLN throughout tumour growth. | |
| Hargadon et al. (2006) | Evaluation of antigen presentation and CD8+ T cell function in an OVA-expressing melanoma tumour murine model. | Tumour derived antigen can be cross-presented by APCs or directly presented by tumour cells to naïve T cells in TDLN, and this induces CD8+ T cell differentiation. | |
| Dammeijer et al. (2020) | Assessment of TDLN in murine tumour (mesothelioma, melanoma, pancreatic and colon adenocarcinoma) models following TDLN-targeted PD-L1 blockade, correlated with PD-1/PD-L1 interactions in TDLN of non-metastatic melanoma patients (see below). | TDLNs contain tumour specific PD-1+ T cells co-localising with PD-L1 expressing myeloid cells, including cDCs. Selective targeting of PD-L1 TDLN-resident T cells affects a systemic anti-tumour immune response and tumour control. | |
| Salmon et al. (2016) | Assessment of immune cell subsets in a murine melanoma model following PD-L1 blockade. | CD103+ DCs, presenting tumour antigen in the TDLN were able to promote tumour specific antigen mediated T cell activation and proliferation. Expansion of CD103+ DCs following poly I:C administration enhanced tumour response to BRAF or PD-L1 blockade. | |
| Tumour specific T cell activation and proliferation | Fransen et al. (2018) | Murine models of colon adenocarcinoma treated with anti-PD-1 and PD-L1 therapy. | TDLNs, but not non-draining LNs, contained CD11b+ myeloid cells with higher levels of PD-L1 expression and increased numbers and activation of CD8+ T cells after anti-PD-1 therapy. Surgical resection of TDLN and inhibition of lymphocyte trafficking from LN abolished therapy induced tumour responses. |
| Principe et al. (2020) | Murine tumour models (mesothelioma, renal cell carcinoma) were treated with anti-CTLA-4 and anti-PD-L1 therapy then tumours and TDLN assessed for immune cell infiltration and profiling. | ICI therapy increased the proliferation of antigen-specific cytotoxic T cells with an effector memory phenotype both in the tumour and TDLN, and correlated with ICI response. | |
| Chamoto et al. (2017) | Murine tumour models (colon adenocarcinoma, lung carcinoma and fibrosarcoma) treated with anti-PD-L1 and targeted therapies. | Resection of TDLNs prior to tumour implantation and/or prior to anti-PD-1 treatment completely abolished or reduced efficacy respectively. CTLs in TDLNs express other targets (e.g. MTOR) which can be drugged to provide synergistic responses with anti-PD-1 therapy. | |
| Liu et al. (2016) | Murine models of breast cancer treated with neoadjuvant or adjuvant immunotherapy. | Neoadjuvant immunotherapy gave greater therapeutic efficacy compared with adjuvant treatment, and correlated with sustained peripheral anti-tumour immune responses. | |
| Migration of immune cell populations from TDLN to the TME | Spitzer et al. (2017) | Murine breast cancer model treated with anti-PD-1 therapy and other immunotherapies. Immune cell responses were analysed from multiple tissues using mass cytometry. Results were correlated with melanoma patients responding to immunotherapy. | T reg, CD8+ T cells and CD4+ effector memory T cells had significantly increased proliferation demonstrating the initiation of a T cell-mediated immune response within the TDLN. In addition, memory T cells were able to activate naïve T cells in the TDLN for a sustained immune response. This CD4+ T cell subset was also found in the peripheral blood of patients with melanoma responding to anti-CTLA-4 + GM-CSF therapy. |
| Fransen et al. (2018) | Murine models of colon adenocarcinoma treated with anti-PD-1 and PD-L1 therapy. | The inhibition of trafficking of T cells from the TDLN decreased T cell numbers in peripheral circulation and correlated with reduced efficacy of anti-PD-1 treatment. In addition, when TDLN were removed prior to therapy with anti-PD-1, the number of CD8+ T cells in the TME was reduced. | |
| Immune tolerance in the TDLN | Watanabe et al. (2008) | Murine fibrosarcoma model receiving adoptive cell transfer with MDSCs from tumour bearing mice or normal splenocytes and stimulated with inoculation of tumour cells. | Immunosuppressive MDSCs have been isolated in TDLN and shown to dampen anti-tumour T cell responses, reducing T cell activation and CD4+/CD8+ T cell numbers but not T cell effector function. |
| Huang et al. (2017) | Assessment of TDLN in a murine breast carcinoma model. | TGF-beta secreting Tregs within TDLNs suppress tumour specific CD8+ T cell cytotoxic activity, resulting in tumour growth. Surgical resection of TDLN reduced distant metastasis. | |
| Alonso et al., (2018) | Assessment of TDLN in a murine lung adenocarcinoma model. | In early tumour development, CD4+ T cells are driven to differentiate as Tregs rather that effector CD4+ T cells in the TDLN, promoting suppressive Treg responses that mimic peripheral self-tolerance to tumour antigen. | |
| Clinical studies | Study | Tumour type | Conclusions |
| Kohrt et al. (2005) | Assessment of sentinel and axillary lymph nodes in breast cancer patients. | Presence of CD4+ T cells and DCs in TDLN correlate with disease free survival. | |
| Nunez et al. (2020) | Assessment of tumour invaded and non-invaded TDLNs in breast cancer patients. | T reg cells traffic from cancer TDLN to the TME. | |
| Sluijter et al. (2015) | Melanoma tumour and sentinel lymph node assessment following randomised trial of intradermal CpG-B/GM-CSF. | The human equivalent CD141+ CLEC-9A+ DCs have been found in TDLNs and were responsible for the cross presentation and activation of anti-tumour T cells in melanoma patients. | |
| Dammeijer et al. (2020) | PD-1/PD-L1 interactions in TDLN of non-metastatic (stage II) melanoma patients, correlated with findings in TDLN in murine tumour models following TDLN-targeted PD-L1 blockade (see above). | PD-1/PD-L1-interactions in TDLNs of non-metastatic melanoma patients, but not in the corresponding primary tumours, are associated with early distant disease recurrence. | |
| Kamphorst et al. (2017) | Assessment of peripheral blood from NSCLC patients following anti-PD-1 therapy, correlated with in vivo findings following anti-PD-1 therapy in a murine model of colon carcinoma. | CD28/B7 mediated proliferation of CD8+ T cells is required for anti-tumour efficacy and occurs in TDLNs. | |
| van de Ven et al. (2017) | Assessment of endobronchial fine needle aspirates from TDLN in NSCLC patients. | TDLN has a greater number of tumour-antigen experienced immune cells and specific activated T cell subsets than peripheral blood sampling. | |
| Shariati et al. (2020) | Assessment of TDLN in breast cancer patients. | CD86+ B cells in TDLN were associated with higher tumour grade and a greater number of metastatic lymph nodes. Expression of PD-1 and CD39 on B cells in LNs correlated with higher grade and larger tumours respectively. Patients with CD73+ B cells had fewer involved lymph nodes. | |
| DeFalco et al. (2018) | Assessment of peripheral blood samples from metastatic melanoma, renal cell carcinoma and lung adenocarcinoma patients. | High levels of blood plasmablasts were found in patients with stable metastatic disease, suggesting that B cell responses may be important for tumour control. |