In mice with either MC38 or CT26 colon tumors, the presence of the tumor-draining lymph nodes (TDLNs) was crucial to the antitumor efficacy of anti-PD-1/anti-PD-L1 treatment. PD-1 blockade led to an increase in total as well as activated CD8+ T cells in the TDLNs. Resection of the TDLNs before anti-PD-1/anti-PD-L1 treatment strongly reduced survival, while removal of the TDLNs prior to tumor inoculation, or locking T cells within lymphoid organs completely abrogated the efficacy of PD-1/PD-L1 blockade, suggesting that the success of this treatment relies on T cells from outside of the TME and on reinvigoration of antigen-specific T cells in TDLNs.
PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8+ T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit.