A new study by Huang et al. in Cell identified the presence of tumor-specific memory CD8+ T cells in tumor-draining lymph nodes (TdLNs) and confirmed the critical role of this population in PD-1/PD-L1 immune checkpoint therapy for cancer.1 The work enriched our understanding of tumor-specific CD8+ T cell subsets and further refined the spatiotemporal mechanism of the antitumor effects of PD-1/PD-L1 immune checkpoint blockade (ICB).

PD-1 and PD-L1 ICB have made remarkable achievements in antitumor therapy. A traditional theory represents the major mechanism by which PD-1/PD-L1 ICB reactivates exhausted CD8+ T cells (TEX) in tumor microenvironment (TME), thereby restoring the autologous antitumor immunity.2 However, this theory cannot explain why only a portion of TEX can response to PD-1/PD-L1 ICB and even “cold” tumors responses to ICB. More recently, accumulating studies point out that immune microenvironment of TdLNs may be a theoretical supplement for TME.3 At present, the study on the role of TdLNs in immunotherapy has just started. Huang’s work provides us with a new perspective on studying TdLNs.

Utilizing orthotopic and subcutaneous tumor mouse models, Huang et al. detected a group of memory CD8+ T cells in TdLNs that expressed TCF1+ TOX- PD-1low. This group of identified CD8+ T cells was consistent in features of memory T cells, such as high expression of canonical memory-associated markers (CD127, CD122, and CD62L), semblable transcriptome and epigenome characteristics, as well as low expression of PD-1. Therefore, they named these cells tumor draining lymph node derived tumor-specific memory T cells (TdLN-TTSM). Significantly, compared with progenitor of exhausted T cells (TPEX) in TdLN and TME, TTSM had a greater proliferation potential comparable to that of memory cells and exhibit an increased capability on antitumor.

Remarkably, authors next demonstrated that TdLN-TTSM also existed in tumor draining lymph nodes from patients who suffered hepatocellular carcinoma. According to T cell receptor clonal comparison and pseudotime trajectory analysis, TdLN-TTSM showed a developmental trajectory of TPEX cells differentiated into tumor infiltrates and exhausted T cells, suggesting that TdLN-TTSM may also play an important antitumor role in cancer patients.

To further investigate the antitumor effects of TdLN-TTSM, TdLN-TTSM and other two tumor-specific CD8+ T cell subsets including TME-TEX and TPEX were adoptively transferred into tumor-bearing mice respectively. TdLN-TTSM cells showed the most significant effect on inhibiting tumor growth.

Notably, TdLN-TTSM was shown to be a key response cell for PD-1/PD-L1 ICB therapy compared with TdLN-TPEX cells through both in vivo and in vitro experiments. Further, lymphadenectomy resulted in the failure of PD-L1 blocking antibody-mediated immunotherapy before or during PD-L1 ICB treatment. However, this effect was able to be restored by denovo transfusion of TdLN-TTSM cells, which further verified that TdLN-TTSM was a bona fide cell subgroup responding to PD-L1 ICB.

In summary, these data established the presence and role of the TdLN-TTSM in generating primary antitumor immune responses following anti-PD-1/PD-L1 ICB, besides providing insights into the spatio-temporal mechanism of PD-1/PD-L1 ICB against tumor (Fig. 1a). Importantly, this work led us to profound reflection.

Fig. 1
Fig. 1The alternative text for this image may have been generated using AI.
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a The mechanism of tumor draining lymph nodes-tumor specific memory T cells (TdLN-TTSM) response to PD-1/PD-L1 immune checkpoint blocking. As a precursor of TdLN-progenitor of exhausted T cells (TPEX), TTSM is located upstream of differentiation and persistently recruit various exhausted T cell subpopulation located in the tumor microenvironment (TME). The antitumor effect of PD-1/PD-L1 antibody is dependent on TTSM cell subsets. The prerequisite for antitumor effect of PD-1/PD-L1 antibody is to first amplify TTSM cell in draining lymph nodes, meanwhile promoting the differentiation into TPEX which subsequently differentiate into exhausted CD8+ T cells (TEX). Finally, the progeny of these cells enters TME through peripheral circulation and plays an antitumor role. Created with BioRender.com. b A summary of published studies on stemlike memory CD8+ T cells which have similar functions to TdLN-TTSM. TdLN-TTSM tumour-draining lymph nodes-tumor specific memory T cells, N.S. nothing special, TSL stem-like T cells, LCMV lymphocytic choriomeningitis virus, NSCLC non-small cell lung cancer, TPEX progenitor of exhausted T cells, ICB immune checkpoint blockade

First, to dig into stemlike memory CD8+ T cells, we summarized previous literature that confirmed the presence of intra or extra-tumoral stemlike memory T cell which had broadly similar functions to TdLN-TTSM (Fig. 1b). In contrast to cells from other research, TdLN-TTSM were shown to be free of exhaustion associated epigenetic scars, suggesting this population was a steady resident in TdLN. It is well known that tumor escape caused by T cell exhaustion is the main cause limiting the efficacy of chimeric antigen receptor (CAR) T cell therapy.4 This study implied that TdLN-TTSM may be a promising candidate of CAR T cell therapy, correspondingly, TdLN which removed by surgery may become a more suitable source of CAR T cell in place of peripheral blood (PB).

Next, as a bona fide cell responding to PD-1/PD-L1 ICB, proportion of TTSM in TdLN may be a novel predictable biomarker of effect after ICB to enable identification of patients in need of alternative treatment strategies. Future studies should focus on confirming the particular marker and existence of TTSM on various tumor types, as well as investigating a potential role in progression and outcome of different pathological types and stages. Moreover, the percentage of TTSM in TdLN, non-TdLN and PB should also be detected in future work.

More importantly, based on the impressive data from adoptive transfer study of TdLN-TTSM in animal model, TdLN-TTSM was a potential choice of adjuvant or combination therapy. Clinical application of immunotherapy by utilizing this population from TdLN should be more explored to potentiate ICB therapy in a real-world setting.

Last not least, this work led us to a renewed look at the effect of TdLN in oncological surgery. To prevent the spread of tumor cells in patients undergoing surgical treatment, complete lymphadenectomy has been well accepted as a traditional clinical practice. However, assisted by the development of ICB therapy, especially PD-1/PD-L1 ICB, reassessment of optimal strategy of lymphadenectomy is clearly warranted. A study from Fear et al. indicated that LN resection may impair the efficacy of adjuvant immunotherapy in a pre-clinical model.5 According to Huang’s research, we inferred leaving tumor-free lymph nodes intact during operation may enable patients to benefit from PD-1/PD-L1 ICB therapy. Further study needs to be performed to verify speculation mentioned above.