In this paper, we report that an intratumoral immune niche, made up of stem-like CD8 T cells and antigen presenting cells, is required to support the CD8 T cell response to cancer.
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Measuring T cell infiltration has been powerful in predicting outcomes in many cancers, but this association has been unclear in kidney cancers. Here, we show that high levels of infiltration CD8 T cells significantly predicts patient progression free survival.
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Patients with more T cells progress 4x less rapidly than those with few T cells, which could have important implications for clinical care (Fig 1b). But we also wanted to ask a more basic question: Why do some patients’ tumors have many T cells, while others have so few?pic.twitter.com/U3sDXhox3E
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What we found was that tumor infiltrating T cells contain 2 important subpopulations: Tim3+ terminally differentiated (TD), effector like cells and TCF1+ stem-like CD8 T cells (Fig 1c).pic.twitter.com/l4tQTeeZNq
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When sorted from human tumors, these stem-like cells consistently proliferate upon stimulation, while the TD cells lack proliferative potential. Upon division, stem-like cells upregulate checkpoint and effector molecules, suggesting their differentiation into TD cells (Fig 1e,g)pic.twitter.com/FAqKjCmi30
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That the stem-like cells give rise to the TD cells is also illustrated by the clonal overlap seen between these populations when their TCR repertoires are sequenced (Fig 1i). (Thank you to
@AdaptiveBiotech for my young investigator grant to make this possible!)pic.twitter.com/diIfodyMNZ
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Interestingly, there was also clonal overlap between stem-like and TD populations in disparate locations within the same tumor (Ext Data 4g).
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We also used RNAseq to examine these populations. The TD cells express high levels of checkpoints and effector molecules, while stem-like cells express higher levels of co-stim and survival genes (Fig 2a).pic.twitter.com/2PrYNlGpF5
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These populations are analogous to those stem-like and TD populations seen in mouse chronic viral infx (Fig 2b).pic.twitter.com/B1wtqanjw6
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Importantly, both stem-like and TD cells are distinct from human yellow fever specific memory & effector T cells – when compared to these populations, they are more similar to effector cells, reflecting their continued, active response in the presence of antigen (Ext Data 5a-e).pic.twitter.com/HcsRG1Aeyt
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This finding—that a stem-like CD8 population resides *in* the tumor—surprising. In mouse models of chronic infection, analogous cells are only found in lymphoid tissue.
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So, we hypothesized that a lymphoid-like microenvironment may support these stem-like cells in the tumor and subsequently looked for antigen presenting cells (APCs) in the tumor tissue.
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We found a strong correlation between tumor infiltrating CD8 T cells and dendritic cells (Fig 3b), a type of APC, which prompted us to use immunofluorescence to see the spatial relationship between these cells.
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We found that stem-like T cells were preferentially found in regions with dense aggregations of MHC-II+ cells (which are APCs), while the TD cells were more dispersed throughout the tissue (Fig 3c).pic.twitter.com/B1AIcBHNPe
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This suggested to us that the stem-like cells were living in lymphoid-like niches with APCs, somewhat like setting up a lymph node like microenvironment in the tumor.
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We also quantified the immunofluorescence data we collected—creating ‘immunomaps’ that show the location of cells of interest and allowing for measurement of staining intensity in single cells (Fig 3d). For techniques, see Ext Data 6c and our methods section.pic.twitter.com/Ych0NwbMB4
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We used these quantification techniques to correlate IF-based measurements of T cell infiltration with our measurements by flow cytometry in the same patients (Ext Data 9c), which confirmed that patients with high CD8 T cell infiltration by flow also had high infiltration by IF.pic.twitter.com/8MudW0cG1g
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We also found that it was critical to sample >100 random 20x fields of view before there was a strong correlation w/ whole tissue analysis (Ext Data 9d). This highlights how vital it is to sample large areas of tumor to get an accurate quantification of infiltration into tumors.pic.twitter.com/fgukbe20Ru
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When we compared APC density across this cohort, patients w/o progressive disease had many areas with high APC density, whereas patients whose disease progressed had fewer of these areas (Fig 4f), reflecting an absence of stem-like T cell/APC niches in the tumor (Fig 4d, h).pic.twitter.com/QfDfy0YG36
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Stratifying patients into those with MHC-II dense or MHC-II sparse tumors, we find that PFS is improved in patients with MHC-II dense tumors (Fig 4g). This could indicate a mechanism of immune escape, where tumors prevent or destroy intratumoral immune niches.pic.twitter.com/eNeEKmYSgD
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In summary, we found that tumor infiltrating T cells are comprised of functionally distinct subsets—TCF1+ stem-like cells and TD cells that express high levels of checkpoint and effector molecules.
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We propose that these stem-like cells give rise to TD cells, and that these stem-like cells require regions of dense APCs (perhaps similar to a T cell zone of a LN) to survive in the tumor.
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While I focused on our findings in kidney cancer here, we found similar results in bladder and prostate cancers and TCF1+ TILs have been identified in other tumor types (e.g. Sade Feldman, Cell, 2018), suggesting that this model is relevant across multiple tumor types.
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So, based on our results, we propose that the decline of intratumoral T cell responses may not be due to an accumulation of checkpoints or PDL1 expression (Ext Data 10), but rather, by the failure of stem-like CD8 T cells to be stimulated to produce many anti-tumor TD cells.
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Our finding that these nests of closely associated T cells and APCs are scarce in tumors progressing rapidly after surgery may also suggest that destruction or prevention of formation of these niches may be a novel mechanism of tumor immune evasion.
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We think that further investigating the mechanisms of a) how and where stem-like cells originate and b) how tumors may destroy or inhibit these intratumoral immune niches will provide avenues for improving patient care in the future.
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Finally, none of this work would be possible without our funding sources, without very many wonderful colleagues and friends, and particularly and importantly without the kind contributions of our patients and their families—we could not do this with you!
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Thank you to funding sources:
@PCF_Science,@PCFnews,@NIH,@AdaptiveBiotech, Swim Across America, and The Cox Foundation.Prikaži ovu nit -
Thank you to our wonderful coauthors and collaborators!
@HaydnKissick@nataliya_pro_@virajmaster@JennyCarlisleMD@DrMartinSanda@MariaAn09407310@bilenma@sowalsky@chrisfilson@s_wilkinson88 (and all the other#twitterless friends!)Prikaži ovu nit - Kraj razgovora
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