Editors' ChoiceCancer

Lymph nodes: The cradle for antitumor immunity

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Science Translational Medicine  21 Oct 2020:
Vol. 12, Issue 566, eabe9219
DOI: 10.1126/scitranslmed.abe9219


Tumor-draining lymph nodes control tumor-specific immune responses induced by anti–PD-L1 therapy.

Immune checkpoint blocking drugs (ICBs), including anti–PD-L1, are paradigm-shifting treatments for cancer. However, the specific cellular, molecular, and spatial mechanisms of ICB efficacy remain to be illuminated. Although there is a general belief that ICBs primarily act in the tumor microenvironment, accumulating evidence challenges this dogma. For instance, it has been shown that intratumoral T cell exhaustion is largely irreversible and that ICBs induce novel clonotypes distinct from tumor-resident T cells. Furthermore, PD-L1 expression on tumor cells is not a perfect predictive biomarker for clinical responses to ICBs.

To determine whether the immune macroenvironment outside of the tumor, particularly in tumor-draining lymph nodes (TDLNs), play a role in regulating the function of ICBs, Dammeijer et al. characterized the abundance of tumor-specific PD-1+ T cells in TDLNs from various tumor models. Their results indicate that TDLNs, like tumors, are enriched with PD-1+ T cells as compared to non-TDLNs. Using an adoptive transfer system with tumor antigen-specific T cells, the authors further showed that these T cells first homed to TDLNs, up-regulated PD-1, and gained effector functions prior to trafficking to tumors. To unequivocally demonstrate a direct role of TDLNs in anti–PD-L1 therapy, the authors adopted two complementary approaches. First, they administered low-dose anti–PD-L1 intrapleurally, which restrains the availability of anti–PD-L1 to TDLNs. This selective targeting of TDLNs effectively suppressed tumor growth, prolonged survival, and enhanced T cell activation. Second, they applied the S1P receptor antagonist, FTY720, to block T cell egress from TDLNs to the tumor site and found this abrogated anti–PD-L1 effects on T cells. Finally, the investigators wanted to identify which PD-L1–expressing cell population in TDLNs interacted with PD-1+ T cells. Through pharmacological depletion of macrophages in TDLNs and visualization of cellular colocalization, they attributed therapeutic effects of anti–PD-L1 to the interaction of PD-L1+ conventional dendritic cells with T cells. Moreover, they showed that PD-1/PD-L1 interactions in TDLNs, but not tumors, directly correlate with worse prognosis of patients with stage II melanoma, highlighting the clinical relevance of their findings.

In summary, this study reveals an essential role of TDLNs in orchestrating the therapeutic response of anti–PD-L1. Given these findings, it would be interesting to know whether TDLNs also coordinate therapeutic efficacy of other ICBs, such as anti–CTLA-4 and anti–PD-1. Further, whether this holds true in a metastatic tumor setting remains to be determined.

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