Memory T Cells in Draining Lymph Nodes Potentiate Anti–PD-L1 Therapy

Immune checkpoint blockade (ICB) can enhance an antitumor immune response by reversing the exhaustion phenotypes acquired by tumor-reactive CD8⁺ T cells within the tumor microenvironment (TME). However, the extent to which tumor-reactive CD8⁺ T cells outside of the TME are impacted by ICB and influence the response to immunotherapy remains incompletely understood. To address this, Huang, Wu, Wang, Chen, and colleagues utilized a model in which mice were injected with murine melanoma cells expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein, followed by the adoptive transfer of naïve T cells harboring a transgenic T-cell receptor specific to an LCMV glycoprotein epitope. Longitudinal flow cytometry analysis indicated the early establishment of a population of tumor-specific TCF-1⁺ CD8⁺ T cells within the tumor draining lymph node (TdLN) that functionally resembled canonical memory T (T_MEM) cells. Reflecting a memory phenotype, TdLN-derived tumor-specific T_MEM cells were able to persist long-term, undergo a proliferative burst upon antigen rechallenge, and differentiate into functional effector cells. Although the TdLN was comprised of both tumor-specific TCF-1⁺ TOX^– T_MEM cells and TCF-1⁺ TOX⁺ progenitors of exhausted T (T_PEX) cells, only TdLN-residing T_MEM cells robustly proliferated and conferred protection after an antigen rechallenge with LCMV. Strengthening these findings, transcriptomic profiling supported the presence of a tumor-specific T_MEM cell subset in the TdLNs of patients with hepatocellular carcinoma. Notably, when compared with T_PEX cells from the TdLN or exhausted T cells from the TME, adoptive transfer of TdLN-derived T_MEM cells into tumor-bearing mice promoted superior control of tumor growth and markedly extended survival. Moreover, anti–PD-L1 treatment enhanced the expansion and cytokine production of TdLN-residing T_MEM cells, and surgical removal of TdLNs largely abolished the antitumor effects of anti–PD-L1 treatment. In summary, these results reveal an important memory CD8⁺ T-cell population within the TdLN that influences the response to immunotherapy.

Huang Q, Wu X, Wang Z, Chen X, Wang L, Lu Y, et al. The primordial differentiation of tumor-specific memory CD8⁺ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell 2022 Oct 7 [Epub ahead of print].

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