Immune editing shapes the cancer landscape

T-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumor-associated macrophages (TAMs). However, modulating macrophages has proved difficult as the molecular and functional features of M2-TAMs on tumor growth are still uncertain. Here we reported that immunosuppressive M2 macrophages render cancer cells resistant to CD8 + T-cell-dependent tumor-killing refractory ICB efficacy by secreting exosomes. Proteomics and functional studies revealed that M2 macrophage-derived exosome (M2-exo) transmitted apolipoprotein E (ApoE) to cancer cells conferring ICB resistance by downregulated MHC-I expression curbing tumor intrinsic immunogenicity. Mechanistically, M2 exosomal ApoE diminished the tumor-intrinsic ATPase activity of binding immunoglobulin protein (BiP) to decrease tumor MHC-I expression. Sensitizing ICB efficacy can be achieved by the administration of ApoE ligand, EZ-482, enhancing ATPase activity of BiP to boost tumor-intrinsic immunogenicity. Therefore, ApoE may serve as a predictor and a potential therapeutic target for ICB resistance in M2-TAMs-enriched cancer patients. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE from M2 macrophages to the tumor cells confers ICB resistance. Our findings also provide a preclinical rationale for treating M2-enriched tumors with ApoE ligand, EZ-482, to restore sensitivity to ICB immunotherapy.

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“…MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T-cell-based immunotherapies. 21 , 24 , 32 …”

Section: Resultsmentioning

confidence: 99%

M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance

et al. 2023

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“…[ 109 ] It can transmit the “message” from inside the cell to the outside. When harmful substances invade the body, CD8 + T cells will recognize and kill them through the “message.” [ 110 ] MHC II mainly transmits “messages” from outside the cell to the cell, and is only expressed on the surface of some APCs, such as DCs and macrophages, for CD4 + T cells to recognize. If tumor antigens are taken up by APCs and presented to MHC I, so that CD8 + T cells can recognize and kill tumor.…”

Section: Common Indicators For Evaluating Effects Of Adjuvantsmentioning

confidence: 99%

Understanding Structure–Function Relationships of Nanoadjuvants for Enhanced Cancer Vaccine Efficacy

Tan

Ding

Teng

et al. 2022

Adv Funct Materials

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Adjuvant, as an important part of vaccines, can observably enhance the magnitude, breadth and durability of immune responses. Nanoadjuvants, as novel vaccine adjuvants, have shown unique advantages and broad application prospects. This review focuses on nanoadjuvants and their structurefunction relationships as well as cancer therapy applications. First, different kinds of adjuvants are first introduced and organic/inorganic adjuvants are emphatically listed. Second, the mechanisms of adjuvants are expounded, covering reservoir effect, stimulating dendritic cells (DCs) maturity, enhancing antigen uptake/cross-presentation, activating complement and inducing cytokines/chemokines release. Next, the methods to evaluate immune effects of adjuvants, including expressions of antigen presenting/costimulatory molecules, detections of T lymphocytes subtypes, antigen-specific antibodies and cytokine secretion, are summarized. Then the authors emphatically focus on the structure-function relationships of nanoadjuvants, exploring the influence of the size, surface charge, surface ligand, aperture, morphology, and aspect ratio on the immune activities. Finally, the authors briefly discuss the safety of adjuvants and present some representative advances of nanoadjuvants in tumor immunotherapy, photothermal immunotherapy, photodynamic immunotherapy, sonodynamic immunotherapy, chemotherapy or radiotherapy/immunotherapy, chemodynamic immunotherapy and multiple therapies. They hope this review can provide comprehensive understanding and broaden the scopes of nanoadjuvants, thus pave the way to the translation from bench to bedside in the future.

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“…The parameters for such response are permissive and agonistic within systems that otherwise reformulate the cooperative inducement for further loss of antigenicity, as assessed by mutant clones of dividing tumor cells. Immune editing shapes the cancer landscape [16].…”

Section: Co-operabilitymentioning

confidence: 99%

Re-Formulated Immuno-Editing as Agonist and Permissive Elements in Establishment of Foci of Carcinogenesis

Agius

2019

CTOIJ

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Immune editing shapes the cancer landscape

Cited by 9 publications

References 2 publications

M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance

M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity to confer immunotherapy resistance

Understanding Structure–Function Relationships of Nanoadjuvants for Enhanced Cancer Vaccine Efficacy

Re-Formulated Immuno-Editing as Agonist and Permissive Elements in Establishment of Foci of Carcinogenesis

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