Abstract A04: Distant lymphoid organs compensate for ICB efficacy after TDLN dissection
Authors: Zhou Hengbo , O'Melia Meghan , Lei Pinji , Rajotte Johanna J. , Razavi Mohammad Rizi , Baish James , Munn Lance L. , Padera Timothy P. 
Published: December 2022

Abstract
Immune checkpoint blockade (ICB) has been approved to treat many cancers and has shown striking promise. Lymph nodes are secondary lymphoid organs that surveil tissue generated lymph and are critical to generate adaptive immune responses. In addition, lymph borne metastasis to tumor draining lymph nodes (TDLNs) occurs in early stage of cancer. Colonization in LNs can induce systemic tolerance to favor distant metastasis of cancer cells and may serve as a source of distant metastases in preclinic setting. Therefore, LN metastatic burden is a strong prognostic factor for patient outcome. Complete LN dissection (CLND) is often used in the clinic to avoid relapse and metastasis. However, because of severe morbidity and marginal benefits in certain cancers including breast cancer, ovarian cancer, cervical cancer, and melanoma, it is under debate whether CLND is necessary. Due to important role of LNs in adaptive immune response, it is imperative to evaluate the effects of removal of TDLNs on ICB efficacy. Recent work demonstrated that PD-1/PD-L1 interaction between conventional dendritic cells (DCs) (PD-L1+) and tumor-specific T cells (PD-1+) is abundant in TDLNs, but not in non-TDLNs. Selective administration of PD-L1 antibody to TDLNs can improve ICB potency, compared to systemic approach. These data suggest removal of TDLNs can potentially impair ICB outcome. Indeed, anti-PD-1 or anti-4-1BB efficacy can be abolished by TDLN dissection in subcutaneously grafted MC38 (colon adenocarcinoma) or CT26 (colon carcinoma) tumors. However, resected stage III melanoma patients from whom TDLNs are completely removed can still respond and benefit from Ipilimumab (targeting CTLA-4) or Nivolumab (targeting PD-1) treatment, indicating TDLNs are not indispensable for ICB efficacy. Further, compared to highly responsive pre-clinic models, a small portion of cancer patients respond when ICB was used as either first-line treatment or second-line treatment in the refractory setting. This raises the question that, with the current limited response rates (even after biomarker selection), whether SLNB or CLND would reduce survival benefit in clinic. Here, by using breast cancer and melanoma orthotopic models, we demonstrate that neither SLNB nor CLND prevents ICB response, despite the important role of TDLN in anti-tumor responses. Mechanistically, we discovered that, after TDLN resection, antigen can be transported to distal LNs through remodeled lymph drainage and/or blood circulation, which contributes to the residual responsiveness to ICB. Data from ongoing ICB phase III clinic trials demonstrate that patients with LNs resected gained comparable survival benefit from ICB treatment, compared to ones without resection. Altogether, ICB efficacy is not reliant solely on the presence of TDLNs.
Citation Format: Hengbo Zhou, Meghan O'Melia, Pinji Lei, Johanna J. Rajotte, Mohammad Rizi Razavi, James Baish, Lance L. Munn, Timothy P. Padera. Distant lymphoid organs compensate for ICB efficacy after TDLN dissection [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A04.