The primordial differentiation of tumor specific memory CD8 T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes
Source:Lilin Ye
CD8+ T exhaustion is the key reason that resulted in ineffective elimination of malignant tumors. Currently, blocking antibodies targeting the PD-1 (Programmed cell death 1, PD-1)/PD-L1 inhibitory signal pathway represent a promising therapy that can reinvigorate exhausted CD8+ T cell to a certain extent and control tumor progression. At present, although this immune checkpoint blockade (ICB) therapy has achieved preferable results in a series of cancer types, it still faces great challenges, such as limited responding cancer species, low overall response rate of patients, and acquired drug resistance. Therefore, the comprehensive understanding of CD8+ T cell response during tumorigenesis and the underlying mechanisms of ICB responsiveness are crucial to further improve the clinical response rate of PD-1 ICB. 

Supported by several grants from National Natural Science Foundation of China (key program 32030041, outstanding youth program 31825011, excellent youth program 82122028, youth program 31900643), Dr. Lilin Ye's team (Institute of Immunology, the Third Military Medical University) and their collaborators confirmed that a substantial proportion of tumor specific CD8+ T cells (CD44+TOX-PD-1loTCF-1+) in the tumor draining lymph nodes, of both mouse tumor models and hepatocellular carcinoma patients, obtained the representative characteristics of classical memory CD8+ T cells, which were then defined as TdLN-TTSM (Tumor Draining Lymph Node Derived Tumor Specific Memory T cell) cells based on their characteristics and localization. 

Moreover, through high-throughput sequencing analysis, the researchers found that the transcriptional profiles of TdLN-TTSM cells were more closely related to classical memory cells at single cell level, but were different from exhausted T cells. Further analysis of ATAC-seq data also leads to consistent conclusions. Recently, exhausted CD8+ T cells were reported to be marked with a set of irreversible changes at the epigenetic level of certain gene loci, known as epigenetic scars. By analyzing the ATAC seq sequencing data of TdLN-TTSM and TdLN-TPEX, they found that TPEX cells from tumor draining LNs and chronic viral infection, and TEX cells from chronic viral infection (Recovery TEX) had comparable chromatin accessibility at multiple sites of Pdcd1and Tox, but these sites were closed in TdLN-TTSM cells, further proving that this specific cell subgroup was not exhausted T cells. Furthermore, both subsets of antigen specific CD8+ T cells from tumor draining lymph nodes were adoptively transferred into tumor bearing mice, respectively. TdLN-TTSM cells showed superior tumor repressive capacity than TPEX and TEX cells. And a series of in vivo adoptive transfer experiments further verified that TdLN-TTSM functioned as the bona fide responds to PD-1/PD-L1 ICB. 

This work was officially published on the top life sciences journal Cell on October 27, 2022. To sum up this research, its innovation is mainly reflected in the following aspects: 1. It breaks the traditional concept that during tumorigenesis, only exhausted T cell forms but no tumor specific memory T cells; 2. It further improved the spatial and temporal mechanism of PD-1 ICB: it first expands TdLN-TTSM cells and further drives these cells to differentiate into progenitor exhausted T cells (TPEX) cells that migrate to the periphery and subsequently differentiate into terminal exhausted T cells (TEX) cells in the tumor micro-environment (TME). In the TME, ICB may sustain the effector function of these newly differentiated TEX cells to effectively execute tumor cells. This conclusion also suggests that the combination of PD-1 ICB and therapies aiming to re-optimize TME may lead to better synergistic anti-tumor effect; 3. During surgeries, doctors may consider to purify and expand TdLN-TTSM cells after the dissection of tumor draining lymph nodes, and then transfer them to patients after surgery, supplemented by immune checkpoint treatment, which may prevent tumor recurrence or metastasis more efficiently; 4. TdLN-TTSM cells are superior to tumor infiltrating T cells (TIL) as candicates in anti-tumor adoptive T cell therapy.

Figure: PD-1/PD-L1 ICB may exert anti-tumor effects in a temporal and spatial manner: it first expands TTSM cells and further drives these cells to differentiate into TPEX cells in TdLNs; subsequently, TdLN-derived TPEX cells migrate to the periphery and finally differentiate into TEX cells in the TME, whereby ICB may sustain the effector function of these newly differentiated TEX cells to effectively execute tumor cells.