Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages

Na, Yi Rang; Kwon, Jung Won; Kim, Da Young; Chung, Hyewon; Song, Juha; Jung, Daun; Quan, Hailian; Kim, Daesik; Ju, YeoJin; Han, Wonshik; Ryu, Han Suk; Lee, Yun Sang; Hong, Jung Joo; Seok, Seonho

doi:10.1016/j.celrep.2020.107643

Cited by 21 publications

(17 citation statements)

References 49 publications

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“…In tumor nests, tumor-derived factors play roles in TAM differentiation. For example, in a recent study, metabolic byproducts of breast cancer activate protein kinase A subunit in macrophages and thereby induce VEGF-A, IL-10, and Arginase-1 secretion that is required for tumor vascularization and immunosuppression (Na et al, 2020). In addition, tumor-derived retinoic acid induces immunosuppressive TAM differentiation in a sarcoma animal model (Devalaraja et al, 2020).…”

Section: Recruitment Of Innate Immune Cells To Primary Tumorsmentioning

confidence: 99%

Redefining macrophage and neutrophil biology in the metastatic cascade

Güç

Pollard

2021

Immunity

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Section: Recruitment Of Innate Immune Cells To Primary Tumorsmentioning

confidence: 99%

Redefining macrophage and neutrophil biology in the metastatic cascade

Güç

Pollard

2021

Immunity

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“…For each experiment, separate batches of tumors were harvested from autochthonous MMTV-PyMT mice (referred to as "inoculum") using an established protocol [56][57][58][59]. Late-stage MMTV-PyMT tumors were harvested, and tumor suspension was either immediately injected into recipient FVB/NJ wild-type mice or frozen for subsequent experiments.…”

Section: Generation Of Syngeneic Modelsmentioning

confidence: 99%

Comparing syngeneic and autochthonous models of breast cancer to identify tumor immune components that correlate with response to immunotherapy in breast cancer

et al. 2021

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Background The heterogeneity of the breast tumor microenvironment (TME) may contribute to the lack of durable responses to immune checkpoint blockade (ICB); however, mouse models to test this are currently lacking. Proper selection and use of preclinical models are necessary for rigorous, preclinical studies to rapidly move laboratory findings into the clinic. Methods Three versions of a common syngeneic model derived from the MMTV-PyMT autochthonous model were generated by inoculating 1E6, 1E5, or 1E4 cells derived from the MMTV-PyMT mouse into wildtype recipient mice. To elucidate how tumor latency and TME heterogeneity contribute to ICB resistance, comprehensive characterization of the TME using quantitative flow-cytometry and RNA expression analysis (NanoString) was performed. Subsequently, response to ICB was tested. These procedures were repeated using the EMT6 breast cancer model. Results The 3 syngeneic versions of the MMTV-PyMT model had vastly different TMEs that correlated to ICB response. The number of cells used to generate syngeneic tumors significantly influenced tumor latency, infiltrating leukocyte populations, and response to ICB. These results were confirmed using the EMT6 breast cancer model. Compared to the MMTV-PyMT autochthonous model, all 3 MMTV-PyMT syngeneic models had significantly more tumor-infiltrating lymphocytes (TILs; CD3+, CD4+, and CD8+) and higher proportions of PD-L1-positive myeloid cells, whereas the MMTV-PyMT autochthonous model had the highest frequency of myeloid cells out of total leukocytes. Increased TILs correlated with response to anti-PD-L1 and anti-CTLA-4 therapy, but PD-L1expression on tumor cells or PD-1 expression of T cells did not. Conclusions These studies reveal that tumor cell number correlates with tumor latency, TME, and response to ICB. ICB-sensitive and resistant syngeneic breast cancer models were identified, in which the 1E4 syngeneic model was most resistant to ICB. Given the lack of benefit from ICB in breast cancer, identifying robust murine models presented here provides the opportunity to further interrogate the TME for breast cancer treatment and provide novel insights into therapeutic combinations to overcome ICB resistance.

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“…Inhibitors of this pathway, used as single agents or in combination with immune checkpoint blockade, promote a pro‐inflammatory and anti‐tumor TAM reprogramming and restored cytotoxic T cell activation 151,152 . An important role of protein kinase A (PKA), a key effector of cAMP signaling, for TAM functions was revealed using models of breast cancer 153 . Specifically, over‐activation of the catalytic activity of PKA induced CREB activation in TAMs and transcription of genes, such as Arg1 , Il10, and Vegfa , typical of immune modulatory and tissue repair programs.…”

Section: Emerging Approaches For Therapeutic Tam Reprogrammingmentioning

confidence: 99%

“…Specifically, over‐activation of the catalytic activity of PKA induced CREB activation in TAMs and transcription of genes, such as Arg1 , Il10, and Vegfa , typical of immune modulatory and tissue repair programs. Targeting of PKA via genetic approaches or pharmacological inhibitors stimulated T‐cell immunity and elicited tumor control 153 . Efficient TME reprogramming could be achieved by targeting chromatin regulators and epigenetic remodelers 154 .…”

Section: Emerging Approaches For Therapeutic Tam Reprogrammingmentioning

confidence: 99%

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

Caronni

Montaldo

Mezzanzanica

et al. 2021

Immunological Reviews

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The tumor microenvironment (TME) is a complex architecture of cells, including those of the immune system, of matrix components, and of their interactions within the unique physical traits of the cancer tissue. 1,2 Many elements influence the composition and cellular dynamics of the TME, such as the anatomical site, the type, and stage of the disease, the therapeutic regimen as well as host factors like age, sex, and comorbidities. 2 Within the extreme diversity of TMEs, parameters integrating the relative composition, spatial arrangement, and functional properties of infiltrating immune cells are useful indicators of disease progression and response to therapies. 2,3 For instance, high tumor infiltration of cytotoxic CD8 + T cells engaging inhibitory crosstalk in the TME via the programmed death (PD)1:PD-L1/PD-L2 axis often predicts efficient response to immune checkpoint blockade therapy. 3 In some cases, CD8 + T cells form organized assemblies with antigen-presenting cells such as dendritic cells (DCs), B cells, and macrophages within the tumor stroma; these so-called tertiary lymphoid structures are considered sites of efficient T-cell priming, and their presence is associated with good response to immunotherapy. 4 In this context, a subset of conventional DCs, termed cDC1, can efficiently cross-present tumor antigens for the induction of a durable immune response. 5-7 Accumulation of cDC1 at the tumor site is mediated at least in part by chemokines released by infiltrating natural killer (NK) cells, 8 a

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Protein Kinase A Catalytic Subunit Is a Molecular Switch that Promotes the Pro-tumoral Function of Macrophages

Abstract: Highlights d The tumor microenvironment increases the activity of PKA-C in macrophages d PKA-Cb specifies pro-tumoral phenotype of macrophages d Macrophages produce pro-tumoral VEGFA, IL-10, and ARG1 via PKA activity d Therapeutic targeting of PKA-C confers anti-tumor T cell responses

Cited by 21 publications

References 49 publications

Redefining macrophage and neutrophil biology in the metastatic cascade

Redefining macrophage and neutrophil biology in the metastatic cascade

Comparing syngeneic and autochthonous models of breast cancer to identify tumor immune components that correlate with response to immunotherapy in breast cancer

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

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