Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Lymph nodes

• Immunotherapy

• Cancer

Main Findings

Cancer patients that receive immunotherapy often also undergo surgical resection of the primary tumor. This typically goes along with removal of the tumor draining lymph nodes (TDLN), but it is still strongly debated if and how this may impact on the efficacy of immune checkpoint blockade (ICB). In this pre-print, Zhou et al. show that resection of TDLN does not reduce efficacy of ICB in mice. Interestingly, they found that TDLN resection relocates anti-tumor immune responses to the closest available lymphoid organs.

The authors used syngeneic mouse models of melanoma (B16F10) and breast carcinoma (E0771) that were treated with ICB, after sentinel lymph node biopsy (SLNB) or complete lymph node dissection (CLND). Interestingly, ICB after SLNB or CLND did not lead to differences in overall survival and tumor outgrowth. This suggests that TDLN resection does not negatively impact on a patient’s ability to raise efficacious anti-tumor immune response, which has important clinical implications.

Fluorescently labelled dextran molecules were used to model antigen distribution, which indicated that antigens end up at the closest available ipsilateral lymphoid organs upon TDLN resection. In contrast, CLND led antigens to be distributed to the contralateral lymph nodes, which was shown to occur by transport through interstitial fluid. In line with this, the use of an orthotopic B16F10-SINFEKKL model revealed that OVA-specific CD8+ T cells expanded in contralateral inguinal (in) LN after CLND, whereas they expanded in ipsilateral inLN in sham operated mice. This relocation of tumor-specific T cells was also shown with a dendritic cell (DC) vaccination approach using OVA-pulsed bone marrow-derived DCs.

The authors propose the interesting idea to mathematically predict how LN dissection changes lymphatic drainage in patients and to use this to guide intranodal administration of antibodies for ICB. Indeed, CLND mice treated intranodally with ICB experienced a greater survival benefit when compared to systemic administration.

Lastly, in a cohort of head in neck cancer patients treated with adjuvant ICB and surgery, complete responders displayed reactive distant lymph nodes even in the absence of metastatic disease, suggestive of on-going immune responses.

Limitations

The authors point out the conserved frequency of OVA-specific T cells in the contralateral in LN of CLND mice when compared to sham mice (figure 4D). Although statistically non-significant, there appears to be a trend towards a lower frequency of activated tumor specific T cells in contralateral lymph nodes of resected mice. This is possibly a limitation of the model used, but considering CLND mice have also have fewer rates of complete responders (figure 1D), it is tempting to argue that there are differences in the efficacy of anti-tumor responses between sham and CLND operated mice, especially since some experiments indicate differences in survival between these two groups (suppl figure 1.A-B, figure 6.D)

Significance/Novelty

Overall, this study reveals that the clinical efficacy of ICB does not critically depend on the presence of TDLN and that, upon resection, their role is taken over by more distant LNs according to yet described predictable patterns. These insights could pave the way to personalised intranodal administration of ICB after LN removal to improve the efficacy of immunotherapy.

Credit

Reviewed by Lucas Baldran-Groves as part of a cross-institutional journal club between the Icahn School of Medicine at Mount Sinai, the University of Oxford, the Karolinska Institute and the University of Toronto.

The author declares no conflict of interests in relation to their involvement in the review.