Prototype of checkpoint response in tumor immunotherapy

preface

Currently, the responsiveness of cancer patients to immune checkpoint blockade (ICB) therapy is predicted by different individual measurements with varying degrees of accuracy, including tumor mutation burden, tumor invasive T cell density, dendritic cell frequency, and checkpoint ligand expression

These are the "seeds" of anti-tumor immunity and are supported

Immune prototype: multiple associated states of functional targets

In living tissue and the immune system, cellular states support

Reactive immune prototypes are collections of cell types that can mediate tumor regression, and the number of cells that make up the reactive immune prototype is sparse and can coexist in tumors that are mainly composed of dominant prototypes

The figure above provides an overview of how a particular cancer type has different tendencies to support a particular response prototype

Class I: PROTOTYPE OF CD8-BASED ICB reactions

CD8+ T cells are characterized by their cell lysis function, which is mediated by interactions between TCR and peptide-MHC I complex (pMHC

Evidence from mouse models of tumor and chronic viral infection suggests that some CD8+ T cell subsets have different depletion states and have the potential to reactivate effector function

How are these CD8+TILs activated? The ability of TME cDC1 in mouse tumors to express a large number of stimulating cytokines IL-12 and maintain intake in a neutral pH environment cross-present tumor antigens on MHC I was also essential for amplifying infiltrated

Finally, a third cell type, Natural Killer (NK) cells, is a key component of

Class II: PROTOTYPE OF CD4-BASED ICB REACTIONS

The direct role

The potential partner of CD4+ T cells in the immune environment of class II reactive tumors is usually cDC2, and in one study, CD11b+cDC2 purified from TME of tumor-bearing mice induced CD4+ T cell expansion and proliferation

Upregulate the pathways of reaction prototypes

What other features of these prototypes remain to be revealed? Here are some other intrinsic and extrinsic factors that may facilitate prototypes of Class I and/or Class II reactions

Reverse T cell depletion

As mentioned earlier, tumor-specific TRM cells and reversing "depleted" T cells can enhance immune archetype reactivity

Presents with genetic modifications

Epigenetics can stabilize TEX cells and prevent cell regeneration, so it may be a determinant

Regulates endoplasmic reticulum stress

Activation of endoplasmic reticulum stress and the unfolded protein response (UPR) contributes to the development and progression

Mast cells

Mast cells (MCs) have a wide range of receptors and symbiostimulatory molecules to respond quickly to afferent signals and secrete various storage and newly synthesized mediators

Microbiome

Mouse studies have shown an association
between gut bacterial taxa and the ICB response.
In one study, a healthy human fecal microbiota (FMT) was transplanted into germ-free mice, resulting in CD8+IFN-γ+T cell expansion and enhanced ICB-mediated anti-tumor immunity
relative to the control group.
In another study, patients with non-small cell lung cancer had an increased responsiveness to CD4 + Th1 in the blood in the presence of mucophilic Ackermania; When comparing ICB-reactive and non-reactive patients, this correlates with improvement in clinical outcomes
.
These results suggest that during ICB treatment, the microbiota can influence key components of class I and ii reactive immune archetypes
.

brief summary

There is substantial evidence that there are at least two "types" of ICB reactivity — Class I and II reactive immune prototypes, whose components already have a well-defined prognosis, and the combination of these traits helps to better predict the reactivity of ICBs
.
A more comprehensive understanding of reactive prototypes also has the potential to adapt preclinical screening platforms, or combine with other approaches to improve tumor cure rates
.

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