Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Li, Jinyang; Byrne, Katelyn T.; Yan, Fangxue; Yamazoe, Taiji; Chen, Zeyu; Baslan, Timour; Richman, Lee P.; Lin, Jeffrey; Sun, Yu; Rech, Andrew J.; Balli, David; Hay, Ceire A.; Sela, Yogev; Merrell, Allyson J.; Liudahl, Shannon M.; Gordon, Naomi; Norgard, Robert J.; Yuan, Salina; Yu, Sixiang; Chao, Timothy; Ye, Shuai; Eisinger-Mathason, T.S. Karin; Faryabi, Robert B.; Tobias, John W.; Lowe, Scott W.; Coussens, Lisa M.; Wherry, E. John; Vonderheide, Robert H.; Stanger, Ben Z.

doi:10.1016/j.immuni.2018.06.006

Cited by 582 publications

(634 citation statements)

References 65 publications

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“…These conflicting results may due to the differences in the tumor‐bearing models used, as IL‐33 appears to work in an environment‐dependent manner. Accumulating evidence suggests that tumor cell‐intrinsic factors underlie the sensitivity of tumor cells to immunologic cytotoxicity . Thus, tumor‐bearing models involving different types of tumor cell may elicit entirely different outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence suggests that tumor cell-intrinsic factors underlie the sensitivity of tumor cells to immunologic cytotoxicity. 44 Thus, tumor-bearing models involving different types of tumor cell may elicit entirely different outcomes. Indeed, in our study, NK cell deficiency completely abolished the IL-33-mediated inhibition of tumor development in 4T1-bearing mice, but not B16-F10-bearing mice.…”

Section: Discussionmentioning

confidence: 99%

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Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Zhang

Miao

et al. 2019

Intl Journal of Cancer

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Increasing evidence suggests that IL‐33 plays an important role in regulating tumor development. However, conflicting results, obtained from numerous studies, have highlighted the divergent functions of IL‐33. The detailed mechanisms by which IL‐33 modulates tumor development merit further investigation. Here, we report that IL‐33 administration can effectively inhibit the development of pulmonary metastasis of breast cancer in a mouse. In our model, IL‐33 promotes the production of TNF‐α by macrophages, which increases IL‐33 specific receptor (ST2) expression on natural killer (NK) cells and is pivotal in IL‐33‐induced NK cell activation. IL‐33 treatment also facilitates the production of CCL5 in the lung by eosinophils and CD8+ T cells, which mediates the recruitment of NK cells to the tumor microenvironment. The systemic activation and local recruitment of NK cells result in potent tumor rejection in the lung. Our study reports a novel mechanism for the IL‐33‐meditated suppression of metastatic cancer and provides potential therapeutic strategies for targeting metastatic tumor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Zhang

Miao

et al. 2019

Intl Journal of Cancer

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“…Taken together, these studies raise the possibility that TP63 functions as an amplifier of NFkB transcriptional output to drive enhanced secretion of inflammatory mediators in squamous subtype PDA tumors. In addition to IL-1α, TP63 promotes expression of other pro-inflammatory cytokines that have been implicated in the development and progression of PDA, such as CXCL1 and GM-CSF (Bayne et al, 2012;Li et al, 2018;Pylayeva-Gupta et al, 2012). Notably, both of these cytokines are also produced by iCAFs, suggesting that the pro-tumorigenic effects of these factors would be amplified by IL-1α-mediated crosstalk between TP63-expressing tumor cells and iCAFs.…”

Section: Discussionmentioning

confidence: 99%

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Somerville

Biffi

Daßler-Plenker

et al. 2019

Preprint

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AbstractA highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans-differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63-dependent manner. These non cell-autonomous effects occur, at least in part, through TP63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

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“…Second, the presence of novel clones suggests an alternative hypothesis for the improved activity of checkpoint blockade agents in immune-infiltrated ('hot') vs immune-desert ('cold') tumors. That is, perhaps the reason that 'hot' tumors respond to therapy is due to an intrinsic ability of the tumor to constantly attract new T cells 56 , rather than the presence of pre-existing T cells in the tumor. Therefore, therapeutic agents that improve recruitment or infiltration of T cells into the tumor might be sufficient to rescue therapeutic responses in cold tumors.…”

Section: Discussionmentioning

confidence: 99%

Clonal replacement of tumor-specific T cells following PD-1 blockade

Yost

Satpathy

Wells

et al. 2019

Preprint

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Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA-and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) preand post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8 + CD39 + T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8 + T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.

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Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy

Cited by 582 publications

References 65 publications

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Interleukin‐33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Clonal replacement of tumor-specific T cells following PD-1 blockade

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