Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma:Relation to the immune cycle

BACKGROUND Various histological types of gastric carcinomas(GCs)differ in terms of their pathogenesis and their preexisting background,both of which could impact the tumor immune microenvironment(TIME).However,the current understanding of the immune contexture of GC is far from complete.AIM To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODS In total,50 GC cases were examined(15 cases of diffuse GC,31 patients with intestinal-type GC and 4 cases of mucinous GC).The immunophenotype of GC was assessed and classified as immune desert(ID),immune excluded(IE)or inflamed(Inf)according to CD8+cell count and spatial pattern.In addition,CD68+and CD163+macrophages and programmed death-ligand 1(PD-L1)expression were estimated.RESULTS We found that GCs with different histological differentiation demonstrated distinct immune contexture.Most intestinal-type GCs had inflamed TIMEs rich in both CD8+cells and macrophages.In contrast,more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+lymphocytes but abundant CD68+macrophages,while mucinous GC had an IE-TIME with a prevalence of CD68+macrophages and CD8+lymphocytes in the peritumor stroma.PD-L1 expression prevailed mostly in intestinal-type Inf-GC,with numerous CD163+cells observed.Therefore,GCs of different histological patterns have specific mechanisms of immune escape.While intestinal-type GC was more often related to PD-L1 expression,diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSION These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

Roles of macrophages in tumor development: a spatiotemporalperspective

Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we knowthat TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just beingunraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized rolesassociated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enablethe growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth.Finally, we speculate on the challenges that remain to be overcome in TAM research.

Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: Dual targeting of tumor cells and tumor-associated macrophages

Combination of passive targeting with active targeting is a promising approach to improve the therapeutic efficacy of nanotherapy.However,most reported polymeric systems have sizes above100 nm,which limits effective extravasation into tumors that are poorly vascularized and have dense stroma.This will,in turn,limit the overall effectiveness of the subsequent uptake by tumor cells via active targeting.In this study,we combined the passive targeting via ultra-small-sized gemcitabine(GEM)-based nanoparticles(NPs)with the active targeting provided by folic acid(FA)conjugation for enhanced dual targeted delivery to tumor cells and tumor-associated macrophages(TAMs).We developed an FAmodified prodrug carrier based on GEM(PGEM)to load doxorubicin(DOX),for co-delivery of GEM and DOX to tumors.The co-delivery system showed small particle size of~10 nm in diameter.The ligand-free and FA-targeted micelles showed comparable drug loading efficiency and a sustained DOX release profile.The FA-conjugated micelles effectively increased DOX uptake in cultured KB cancer cells that express a high level of folate receptor(FR),but no obvious increase was observed in 4T1.2 breast cancer cells that have a low-level expression of FR.Interestingly,in vivo,systemic delivery of FAPGEM/DOX led to enhanced accumulation of the NPs in tumor and drastic reduction of tumor growth in a murine 4T1.2 breast cancer model.Mechanistic study showed that 4T1.2 tumor grown in mice expressed a significantly higher level of FOLR2,which was selectively expressed on TAMs.Thus,targeting of TAM may also contribute to the improved in vivo targeted delivery and therapeutic efficacy.

The soluble glycoprotein NMB(GPNMB)produced by macrophages induces cancer sternness and metastasis via CD44 and IL-33

In cancer,myeloid cells have tumor-supporting roles.We reported that the protein GPNMB(glycoprotein nonmetastatic B)was profoundly upregulated in macrophages interacting with tumor cells.Here,using mouse tumor models,we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice(DBA/2J).GPNMB triggers in the cancer cells the formation of self-renewing spheroids,which are characterized by the expression of cancer stem cell markers,prolonged cell survival and increased tumor-forming ability.Through the CD44 receptor,GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor UR1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells.Overall,our results reveal a new paracrine axis,GPNMB and IL-33,which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival,the expansion of cancer stem cells and the acquisition of a metastatic phenotype.

A targeting black phosphorus nanoparticle based immune cells nanoregulator for photodynamic/photothermal and photo-immunotherapy

Photo-immunotherapy is a novel therapeutic approach against malignant tumors with minimal invasiveness.Herein,a targeting multifunctional black phosphorus(BP)nanoparticle,modified by PEGylated hyaluronic acid(HA),was designed for photothermal/photodynamic/photo-immunotherapy.In vitro and in vivo assays indicated that HA-BP nanoparticles possess excellent biocompatibility,stability,and sufficient therapeutic efficacy in the combined therapy of photothermal therapy(PTT)and photodynamic therapy(PDT)for cancer therapy.Moreover,the results of in vitro showed that HA-BP down-regulated the expression of CD206(M2 macrophage marker)by 42.3%and up-regulated the ratio of CD86(M1 macrophage marker)by 59.6%,indicating that HABP nanoparticles have functions in remodeling tumor associated macrophages(TAMs)phenotype(from protumor M2 TAMs to anti-tumor M1 macrophages).Fluorescence(FL)and photoacoustic(PA)multimodal imaging confirmed the selective accumulation of HA-BP in tumor site via both CD44^+mediated active targeting and passive EPR effect.In vitro and in vivo studies suggested that the combined therapy of PDT,PTT and immunotherapy using HA-BP could not only significantly inhibit original tumor but also induce immunogenic cell death(ICD)and release Damage-associated molecular patterns(DAMPs),which could induce maturation of dendritic cells(DCs)and activate effector cells that robustly evoke the antitumor immune responses for cancer treatment.This study expands the biomedical application of BP nanoparticles and displays the potential of modified BP as a multifunctional therapeutic platform for the future cancer therapy.