A Pan-Cancer Census of Dominant Tumor Immune Archetypes

Combes, Alexis J.; Samad, Bushra; Tsui, Jessica; Chew, Nayvin W.; Yan, Peter; Reeder, Gabriella C.; Kushnoor, Divyashree; Shen, Alan; Davidson, Brittany; Barczak, Andrea J.; Adkisson, Michael; Edwards, Austin; Naser, Mohammad; Barry, Kevin C.; Courau, Tristan; Hammoudi, Taymour M.; Argüello, Rafael J.; Rao, Arjun A.; Olshen, Adam B.; Consortium, The Immunoprofiler; Cai, Chen; Zhan, Jenny; Davis, Katelyn; Kelley, Robin K.; Chapman, Jocelyn; Attreya, Chloe E.; Patel, Amrish; Daud, Adlil; Ha, Patrick K.; Diaz, Aaron A.; Kratz, Johannes R.; Collisson, Eric A.; Fragiadakis, Gabriela K.; Erle, David J.; Boissonnas, Alexandre; Asthana, Saurabh; Chan, Vincent; Krummel, Matthew F.

doi:10.2139/ssrn.3833003

Cited by 3 publications

(1 citation statement)

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“…Continued understanding of the phenotypic and functional diversity of immune components within the TME has resulted in a greater appreciation for the role of cell types beyond T cells in regulating antitumor immunity (6,(47)(48)(49). There is increasing evidence that suppressive myeloid cell populations limit antitumor immune responses (3)(4)(5)(6).…”

Section: Discussionmentioning

confidence: 99%

TREM1 activation of myeloid cells promotes antitumor immunity

Juric,

Mayes,

Binnewies

et al. 2023

Sci. Transl. Med.

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Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

TREM1 activation of myeloid cells promotes antitumor immunity

Juric,

Mayes,

Binnewies

et al. 2023

Sci. Transl. Med.

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Spatiotemporal co-dependency between macrophages and exhausted CD8⁺T cells in cancer

Kersten

Combes

et al. 2021

Preprint

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T cell exhaustion is a major impediment to anti-tumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here we show that the biology of tumor-associated macrophages (TAM) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAM reduces exhaustion programs in tumor-infiltrating CD8+ T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Tex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8+ T cells engage in unique long-lasting antigen-specific synaptic interactions that fail to activate T cells, but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.

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Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

Mujal

Combes

Rao

et al. 2022

Cancer Immunology Research

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The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid-cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T-cell function and their relationship to patient outcome. Here, we have leveraged single-cell RNA-sequencing analysis of several mouse and human tumors and found that monocyte–macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. We also found in mouse models that tumor monocyte-to-macrophage progression was profoundly tied to regulatory T cell (Treg) abundance. In human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states.

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A Pan-Cancer Census of Dominant Tumor Immune Archetypes

Cited by 3 publications

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TREM1 activation of myeloid cells promotes antitumor immunity

TREM1 activation of myeloid cells promotes antitumor immunity

Spatiotemporal co-dependency between macrophages and exhausted CD8⁺T cells in cancer

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

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A Pan-Cancer Census of Dominant Tumor Immune Archetypes

Cited by 3 publications

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TREM1 activation of myeloid cells promotes antitumor immunity

TREM1 activation of myeloid cells promotes antitumor immunity

Spatiotemporal co-dependency between macrophages and exhausted CD8+T cells in cancer

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

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Spatiotemporal co-dependency between macrophages and exhausted CD8⁺T cells in cancer