TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

Park, Matthew D.; Reyes-Torres, Ivan; LeBérichel, Jessica; Hamon, Pauline; LaMarche, Nelson M.; Hegde, Samarth; Belabed, Meriem; Troncoso, Leanna; Grout, John A.; Magen, Assaf; Humblin, Étienne; Nair, Achuth Sankar S.; Molgora, Martina; Hou, Jinchao; Newman, Jenna H.; Farkas, Adam M.; Leader, Andrew M.; Dawson, Travis; D’souza, Darwin; Hamel, Steven; Sánchez-Paulete, Alfonso R.; Maier, Bárbara; Bhardwaj, Nina; Martin, Jérôme C.; Kamphorst, Alice O.; Kenigsberg, Ephraim; Casanova-Acebes, María; Horowitz, Amir; Brown, Brian D.; Andrade, Lucas Ferrari de; Colonna, Marco; Marron, Thomas U.; Mérad, Miriam

doi:10.1038/s41590-023-01475-4

Cited by 62 publications

(44 citation statements)

References 66 publications

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“…Indeed, cancer cell recognition by naïve LPMs triggers vigorous uptake, followed by an inflammatory and metabolic response that culminates in the presentation of ingested antigens on MHC class-I. The induction of inflammatory genes program also indicates that the uptake of cancer cells, unlike normal apoptotic cells 37 , is not silent and may actually contribute to remodeling of the compartment, as it has been recently described in monocyte-derived macrophages expressing TREM2 38 . Interestingly, the capacity of LPM to cross-present was strongly inhibited in late tumors, which is consistent with an active educational mechanism that shapes resident macrophages towards a pro-tumoral phenotype.…”

Section: Discussionmentioning

confidence: 92%

Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis

Joshi,

Rodríguez,

Morosi

et al. 2023

Preprint

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Cross-presentation of tumor antigens by subsets of macrophages at different stages along tumor progression may have divergent impacts on anti-tumoral immune responses. Here we show that TIM4+ large peritoneal macrophages (LPM) avidly capture tumor cells and cross-present tumor-associated antigens at early stages of peritoneal infiltration by ovarian cancer cells. The phosphatidylserine (PS) receptor TIM4 promotes maximal uptake and triggers inflammatory and metabolic gene programs in combination with cytoskeletal remodeling and upregulation of transcriptional signatures related to antigen processing. At the cellular levels, TIM4 is recruited with F-actin at the phagocytic cup and translocates in nascent phagosomes, controlling the kinetic of phagosomal acidification and cargo degradation. TIM4 deletion abrogates cross-presentation of tumor-associated antigens and blunts expansion of effector CD8 T cells at tumor inception. In addition, targeting tumor antigens to LPM by PS liposomes can trigger CD8 T cell activation. Together these results suggest that TIM4 enables LPMs to scan the antigenic content of incoming tumor cells to promote immune surveillance by CD8 T cells and, at defined temporal windows, may be exploited for therapeutic purposes.

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Section: Discussionmentioning

confidence: 92%

Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis

Joshi,

Rodríguez,

Morosi

et al. 2023

Preprint

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“…Nevertheless, it is tempting to speculate that combining NeoAg vaccines that maintain or promote CX3CR1 + CD206 + macrophages expressing high levels of Trem2 with treatments targeting this macrophage population 42,92 might enhance the efficacy of NeoAg vaccines.…”

Section: Discussionmentioning

confidence: 99%

Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy

Keshari,

Shavkunov,

Miao

et al. 2023

Preprint

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SUMMARYThe goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to eliminate cancer by expanding and/or sustaining intratumoral T cells with enhanced anti-tumor capabilities. However, whether therapeutic cancer vaccination and ICT achieve enhanced anti-tumor immunity by distinct or somewhat overlapping immunological mechanisms remains unclear. Considering increasing interest in combining these two types of treatment to improve efficacy rates, a better understanding of how these treatments are similar and different is needed. Here, we compared effective therapeutic tumor-specific mutant neoantigen (NeoAg) cancer vaccines with anti-PD-1, anti-CTLA-4, or anti-CTLA-4 plus anti-PD-1 combination ICT in preclinical models. We found that both NeoAg vaccines and anti-CTLA-4 and/or anti-PD-1 ICT induced robust expansion of intratumoral NeoAg-specific CD8 T cells, though the degree of expansion and acquisition of effector activity was more substantial following NeoAg vaccine compared to ICT. Further, we found that NeoAg vaccines are particularly adept at inducing proliferating and stem-like NeoAg-specific CD8 T cells. Additionally, anti-CTLA-4 notably induced ICOS+Th1-like CD4 T cells expressing the transcription factor Bhlhe40 and, interestingly, when combined with anti-PD-1 a small subset of Th2-like CD4 T cells was observed. Conversely, we observed a more divergent effect on certain subsets of intratumoral macrophages induced by NeoAg vaccines as compared to ICT. Although effective NeoAg vaccines or ICT expanded M1-like iNOS+macrophages, NeoAg vaccines expanded rather than suppressed (as observed with ICT) distinct subpopulations of M2-like CX3CR1+CD206+macrophages, associated with the poly I:C adjuvant used in the vaccine. Considering the similarities and difference we identified in how NeoAg vaccines versus ICT reshaped the TME, we hypothesized that combining ICT with NeoAg vaccines would expand the therapeutic window for efficacy in these preclinical models. Indeed, we found the combination NeoAg vaccine plus ICT induced superior anti-tumor control compared to either therapy in isolation, highlighting the utility of combining these modalities to eliminate cancer.HighlightsNeoantigen vaccines utilize distinct cellular mechanisms from anti-CTLA-4 or anti-PD-1 immune checkpoint therapy.Neoantigen vaccines preferentially induce PD-1+ TCF1+ stem-like and proliferating neoantigen-specific CD8 T cellsAnti-PD-1 expands PD-1+ TCF-7-NeoAg-specific Teff/Tex, with combination anti-PD-1 + anti-CTLA-4 ICT inducing robust expansion of Bhlhe40hi PD-1+ TCF-7-NeoAg-specific Teff/Tex.Anti-CTLA-4 promotes Th1-like ICOS+ Bhlhe40+ CD4 T cells, while combination anti-CTLA-4 and anti-PD-1 ICT induces a small subset of Th2-like CD4 T cellsNeoantigen vaccines induce partially distinct intratumoral macrophage remodeling from immune checkpoint therapyNeoantigen vaccines in combination with anti-CTLA-4 or anti-PD-1 provides enhanced tumor protection equivalent to or even exceeding protection seen with combination anti-CTLA-4 and anti-PD-1

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“…[ 71 ] Increasing studies have shown the triggering receptor expressed on myeloid cells‐2 (Trem2) is playing a key role in the accumulation of PMN‐MDSCs and TAMs. [ 72 ] Hypoxia is also proven to be mutual stimulative with the polarization of M2‐phenotype TAMs and neutrophil degranulation. [ 73 ] Like common macrophages, TAMs also are divided into M1–M2 phenotypes exhibiting opposite biological functions, among which the M2‐phenotype is in the dominant position.…”

Section: The Immunosuppressive Factors Of Tmementioning

confidence: 99%

Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

Gong,

Jia,

Zhou

et al. 2023

Advanced NanoBiomed Research

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The therapeutic modes of cancers have been profoundly renovated by immunotherapies, which have shown extraordinary treating efficacy in certain tumor entities. However, the majority of cancer patients have not profited from it because of the negative effects of tumor microenvironment (TME) on human innate and/or adaptive immunity, including hypoxia, acidification, irregular vasculature, and a plethora of immunosuppressive cells and small molecules, which contribute to tumor progression, migration, resistance to drug, and so forth. Accordingly, it is feasible to enhance the efficacy of immunotherapies and increase the patients’ survival through the restructure of TME. Herein, the mechanisms and reverberations of aforementioned immunosuppressive elements are concentrated on, and latest therapeutic achievements and combined technologies that have been demonstrated effective in boosting immunotherapies by TME modulation are enumerated.

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TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer

Cited by 62 publications

References 66 publications

Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis

Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis

Neoantigen Cancer Vaccines and Different Immune Checkpoint Therapies Each Utilize Both Converging and Distinct Mechanisms that in Combination Enable Synergistic Therapeutic Efficacy

Enhancing the Treating Efficacy of Immunotherapy through the Restructure of Tumor Microenvironment

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