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T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFN γ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFN γ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFN γ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy. Interferon-gamma (IFNγ) recruits T cells, while Siglec15 on tumor-associated macrophages hampers the proliferation. Reduction-responsive nanoparticles delivering siSiglec15 and IFNγ combined with immune checkpoint inhibitors could inhibit hepatocellular carcinoma growth. [Display omitted] [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes (TILs) is associate with response to immunotherapies. Recent studies have identified TGF β activity and signaling as a determinant of T cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 blockade. Here we coupled the artificial intelligence (AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of TILs and characterize the associated TGF β pathway activity. Analysis of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution patterns. The digital image analysis approach achieves 74% concordance with the pathologist assessment for tumor-immune phenotypes. The transcriptomic profiling suggests that the TIL score was negatively correlated with TGF β pathway activation, together with elevated TGF β signaling activity observed in excluded and desert tumor phenotypes. The present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes: immune desert, immune excluded or immune inflamed. The association between "cold" tumor-immune phenotypes and TGF β signature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGF β blockade. An artificial intelligence-powered digital image analysis approach has been established to characterize and classify the cancer immune phenotypes, which might be utilized as predictive biomarkers for TGF β blockade therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Tumors with a low level of pre-existing immune cell infiltration respond poorly to immune checkpoint therapies. Oncolytic viruses optimize immunotherapies by modulating the tumor microenvironment and affecting multiple steps in the cancer-immunity cycle, making them an attractive agent for combination strategies. We engineered an HSV-1-based oncolytic virus and investigated its antitumor effects in combination with the marketed PD-1 antibody Keytruda (pembrolizumab) in hPD-1 knock-in mice bearing non-immunogenic B16-F10 melanoma. Our results showed enhanced CD8+ and CD4+ T cell infiltration, IFN-γ secretion and PD-L1 expression in tumors, subsequently leading to the prolonged overall survival of mice. Systemic changes in lymphocyte cell proportions were also observed in the peripheral blood. In summary, these findings provide evidence that oncolytic viruses can be engineered as a potential platform for combination therapies, especially to treat tumors that are poorly responsive to immune checkpoint therapy. 1 An oncolytic virus VT09X optimizes the anti-PD-1 antibody therapy in low immunogenic melanoma. 2 Humanized PD-1 knock-in mice were used for in vivo study against melanoma. 3 Stimulation of TIL in local tumors and peripheral blood was performed. 4 Several molecule expressions relative to T cell response such as β2M and IFN-γ were evaluated. [ABSTRACT FROM AUTHOR]

• Low-dose radiation upregulates T cell chemokines and iRGD receptors. • Low-dose radiation improves infiltration and antitumor potency of transferred T cells. • Combining low-dose radiation with adoptive cell therapy is beneficial in solid tumors. Poor penetration of transferred T cells represents a critical factor impeding the development of adoptive cell therapy in solid tumors. We demonstrated that iRGD-antiCD3 modification promoted both T cell infiltration and activation in our previous work. Interest in low-dose radiotherapy has recently been renewed due to its immuno-stimulatory effects including T cell recruitment. This study aims to explore the synergistic effects between low-dose radiotherapy and iRGD-antiCD3-modified T cells. Flow cytometry was performed to assess the expression of iRGD receptors and chemokines. T cell infiltration was evaluated by immunohistofluorescence and in vivo real-time fluorescence imaging and antitumor effects were investigated by in vivo bioluminescence imaging in the gastric cancer peritoneal metastasis mouse model. We found that 2 Gy irradiation upregulated the expression of all three iRGD receptors and T-cell chemokines. The addition of 2 Gy low-dose irradiation boosted the accumulation and penetration of iRGD-antiCD3-modified T cells in peritoneal tumor nodules. Combining 2 Gy low-dose irradiation with iRGD-antiCD3-modified T cells significantly inhibited tumor growth and prolonged survival in the peritoneal metastasis mouse model with a favorable safety profile. Altogether, we demonstrated that low-dose radiotherapy could improve the antitumor potency of iRGD-antiCD3-modified T cells by promoting T cell infiltration, providing a rationale for exploring low-dose radiotherapy in combination of other adoptive T cell therapies in solid tumors. [ABSTRACT FROM AUTHOR]

In immunotherapy, 'cold' tumors, with low T cells infiltration, hardly benefit from the treatment of immune checkpoint inhibitors (ICIs). To address this issue, we screened two 'cold' tumor models for mice with high expression of galectin-3 (Gal-3) and designed a cocktail strategy to actively recruit CD8+ T cells into the tumor microenvironment (TME), which reversed 'cold' tumors into 'hot' and remarkably elevated their ICIs-responsiveness. Gal-3, an important driving force of tumorigenesis, inhibits T cell infiltration into tumor tissue that shapes 'cold' tumor phenotype, and promotes tumor metastasis. In this respect, Gal-3 antagonist G3-C12 peptide was chosen and further loaded into poly(lactic- co -glycolic acid) (PLGA) microspheres, with the prepared G3-C12@PLGA playing a dual role of antitumor, namely, killing two birds with one stone. Specifically, G3-C12@PLGA actively recruit T cells into 'cold' tumors by rescuing IFN-γ, and simultaneously inhibit tumor metastasis induced by Gal-3. Moreover, when combined with chemotherapeutic agent (Oxaliplatin) and anti-PD-1 peptide (APP), the immunopotentiating effect of dendritic cells (DCs) was extremely improved, with T-cell depletion dramatically reversed. In vivo experiments showed that such cocktail therapy exerted remarkable antitumor effect on 'cold' breast cancer (BC) and ovarian serous cancer (OSC). These results indicated that our strategy might be promising in treating 'cold' tumors with high expression of Gal-3, which not only enhance cancer treatment outcome, but provide a new platform for the prevention of postoperative tumor recurrence/metastasis. [Display omitted] • Breast cancer and ovarian cancer were 'cold' tumors with high expression of galectin-3. • G3-C12@PLGA actively recruited T cells into tumors and inhibited tumor metastasis. • Cocktail therapy reshaped the TME, providing a new strategy for curing malignancies. [ABSTRACT FROM AUTHOR]

The infiltration of cytotoxic T lymphocytes promises to suppress the most irresistible metastatic tumor for immunotherapy, yet immune privilege and low immunogenic responses in these aggressive clusters often restrict lymphocyte recruitment. Here, an in situ adherent porous organic nanosponge (APON) doubles as organ selection agent and antigen captor to overcome immune privilege is developed. With selective organ targeting, the geometric effect of APON composed of disc catechol-functionalized covalent organic framework (COF) boosts the drug delivery to lung metastases. Along with a self-cascaded immune therapy, the therapeutic agents promote tumor release of damage-associated molecular patterns (DAMPs), and then, in situ deposition of gels to capture these antigens. Furthermore, APON with catechol analogs functions as a reservoir of antigens and delivers autologous DAMPs to detain dendritic cells, resulting in a sustained enhancement of immunity. This disc sponges (APON) at lung metastasis as antigen reservoirs and immune modulators effectively suppress the tumor in 60 days and enhanced the survival rate. [ABSTRACT FROM AUTHOR]

The acidic metabolic byproducts within the tumor microenvironment (TME) hinder T cell effector functions. However, their effects on T cell infiltration remain largely unexplored. Leveraging the comprehensive The Cancer Genome Atlas dataset, we pinpoint 16 genes that correlate with extracellular acidification and establish a metric known as the "tumor acidity (TuAci) score" for individual patients. We consistently observe a negative association between the TuAci score and T lymphocyte score (T score) across various human cancer types. Mechanistically, extracellular acidification significantly impedes T cell motility by suppressing podosome formation. This phenomenon can be attributed to the reduced expression of methyltransferase-like 3 (METTL3) and the modification of RNA N 6-methyladenosine (m6A), resulting in a subsequent decrease in the expression of integrin β1 (ITGB1). Importantly, enforced ITGB1 expression leads to enhanced T cell infiltration and improved antitumor activity. Our study suggests that modulating METTL3 activity or boosting ITGB1 expression could augment T cell infiltration within the acidic TME, thereby improving the efficacy of cell therapy. [Display omitted] • Tumor acidic score correlates negatively with CD8 infiltration score in human cancers • Extracellular acidification impedes T cell infiltration • Extracellular acidification hinders METTL3-mediated m6A modification in integrin β1 • Modification of CAR-T cells with integrin β1 improves their antitumor activity Wang et al. have identified a correlation between extracellular acidification and limited infiltration of T cells into solid tumors. Elevated extracellular acidification impairs T cell podosome formation by suppressing METTL3-mediated m6A modification, which in turn regulates integrin β1 expression. Integrin β1-modified T cells demonstrated increased infiltration and improved antitumor activities. [ABSTRACT FROM AUTHOR]

• Downregulation of S100A11 promotes T cell infiltration by reducing CAFs in prostate cancer. • The combined knockdown shows a superior therapeutic effect. • Knockdown of S100A11 sensitizes the therapeutic effect of Erdafitinib in vivo. This study aims at revealing the relationship between S100A11 and cancer-associated fibroblasts (CAFs) in prostate cancer and improving T cell infiltration into solid tumors. H&E, IHC and Sirius red staining were used to detect the stroma content in prostate cancer tissues. Stable S100A11 knockdown cell lines DU 145, 22Rv1, RM-1 and NOR-10 were established by lentivirus transfection. Co-culture system of RM-1 and CAFs was established. CCK-8, wound healing and transwell were proceeded to determine proliferation, migration and invasion of prostate cancer cells. Stably knocked-down RM-1 and CAFs were co-injected into C57BL/6 mice to detect the role of S100A11 in vivo. CAFs, CD4+ T cell and CD8+ T cell in these tumors were assessed by IF. T cell profile was analyzed by flow cytometry. A significant amount of stroma exists in prostate cancer tissues. Downregulation of S100A11 inhibits proliferation, migration and invasion of human prostate cancer cells in vitro, and suppresses the expression of cancer-associated fibroblasts (CAFs) in vivo. Knockdown of S100A11 enhances the inhibitory effect of Erdafitinib on CAFs in both the co-culture system and in vivo. The combined knockdown of S100A11 in tumor cells and CAFs shows a superior therapeutic effect compared to the individual knockdown in tumor cells alone. Knockdown of S100A11, both in RM-1 and CAFs, combined with Erdafitinib treatment reduces tumorigenicity by suppressing the content of CAFs and increasing the infiltration of CD4+ T cell and effective CD8+ T cell in tumor. Downregulation of S100A11 plays a crucial role in enhancing the therapeutic response to Erdafitinib and reversing immunosuppressive tumor microenvironment. [ABSTRACT FROM AUTHOR]

Splenic red pulp macrophages play a critical role infiltration of infected RBC and elimination of pathogens during malarial infection. However, the efficiency of pathogenic processing and the intricate pathway followed by them to boost the downstream immune response has not been studied in details. We checked the status of autophagic regulation within the cells both before and after the infection and also modulated the autophagic flux with either its inducer or inhibitor. We found that the upregulation of autophagic gene and the corresponding pathway is correlated with better parasite clearance and survivability, with an enhanced downstream immune response. It also increases their phagocytic potential with better Lysosomal associated protein I and II synthesis. The autophagolysosome formation increases as well, and more vacuole bound LC3B protein are detected. Chemokine synthesized from Red Pulp macrophage helps in mediating the induction for recruiting neutrophil and CD4 + T cells to the splenic red pulp region. The skewing of M1 macrophage polarity is observed post autophagic induction with a better costimulatory molecule like CD80, CD86 expression and antigen presenting molecule MHC I, MHC II is observed. This study shows the possibility of an alternative or adjuvant therapy regimen for the malarial patient by inducing the autophagic pathway that targets the red pulp macrophages. This might be helpful for better pathogen degradation and processing. The subsequent clearance of parasite will result in a better outcome for the patients. Unlabelled Image • Autophagy induced red pulp macrophages activate parasite clearance and enhances survivability in cerebral malaria. • Antigen processing and presentation, co-stimulation activity elicited post autophagic induction. • Induction of chemokine signal for Neutrophil and CD4T cells Infiltration within splenic red pulp zone generated from RPM. [ABSTRACT FROM AUTHOR]

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1–28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2 , and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation. [Display omitted] • Glucose promotes oligomerization and activation of NSUN2 by its direct binding to NSUN2 • The glucose/NSUN2 axis maintains TREX2 expression to execute its oncogenic activity • The axis represses cGAS/STING activation to maintain oncogenic activity of cancer cells • The axis drives anti-PD-L1 immunotherapy resistance by restricting cGAS/STING signaling Whether glucose is a signaling molecule directly regulating oncoproteins for tumorigenesis remains elusive. Chen et al. identify NSUN2 as a direct glucose sensor driving tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation, thus opening a new avenue for studying novel glucose's actions in regulating diverse biological processes. [ABSTRACT FROM AUTHOR]

The insufficient infiltration of T cells in solid tumors hinders the therapeutic efficacy of immune checkpoint blockade (ICB) antibodies and chimeric antigen receptor (CAR)-T cells. Promoting T or CAR-T cells to efficiently and specifically migrate into solid tumors is critical for improving current immunotherapies, which remains a challenge. Herein, we proposed a CRISPR-based transcriptional activation (CRISPRa) nanomedicine for mobilizing tumor cells to recruit T cells by activating the expression of T cell chemokines CXC-chemokine ligand (CXCL) 9, CXCL10, and CXCL11. We demonstrated that the CRISPRa nanomedicine could dramatically upregulate the expression of these T cell chemokines in tumor cells, thereby facilitating T cell migration directionally into solid tumors. Intratumoral injection of the CRISPRa nanomedicine inhibited the growth of different solid tumors including melanoma, pancreatic, colonic, and breast cancers. Moreover, tumor-specific versions of the CRISPRa nanomedicine possessing the ability to upregulate the T cell chemokine expression only in tumors rather than normal tissues or cells were constructed. Systemic injection of the tumor-specific CRISPRa nanomedicine specifically recruited T or CAR-T cells into solid tumors and improved the therapeutic effects of ICB antibodies (anti-PD-L1 or anti-CTLA4) and CAR-T cells. Thus, the gene-activating nanomedicine provides a promising strategy for enhancing T cell infiltration to improve current immunotherapies against solid tumors. [Display omitted] • CRISPRa nanomedicine recruited effector T cells into tumors via activating T cell chemokines. • Tumor-specific CRISPRa nanomedicine could activate only tumors rather than normal organs to express T cell chemokines. • Systemic injection of the tumor-specific CRISPRa nanomedicine enhanced the efficacy of ICB antibodies and CAR-T cells. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Despite intense investigations, little is known about its pathological mediators. Here, we report the marked upregulation of RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin, chemokines that are involved in T cell trafficking, in the serum of hemiparkinsonian monkeys. Interestingly, 1-methyl-4-phenylpyridinium (MPP + ), a Parkinsonian toxin, increased the expression of RANTES and eotaxin in mouse microglial cells. The presence of NF-κB binding sites in promoters of RANTES and eotaxin and down-regulation of these genes by NEMO-binding domain (NBD) peptide, selective inhibitor of induced NF-κB activation, in MPP + -stimulated microglial cells suggest that the activation of NF-κB plays an important role in the upregulation of these two chemokines. Consistently, serum enzyme-linked immuno assay (ELISA) and nigral immunohistochemistry further confirmed that these chemokines were strongly upregulated in MPTP-induced hemiparkinsonian monkeys and that treatment with NBD peptides effectively inhibited the level of these chemokines. Furthermore, the microglial upregulation of RANTES in the nigra of hemiparkinsonian monkeys could be involved in the altered adaptive immune response in the brain as we observed greater infiltration of CD8 + T cells around the perivascular niche and deep brain parenchyma of hemiparkinsonian monkeys as compared to control. The treatment of hemiparkinsonian monkeys with NBD peptides decreased the microglial expression of RANTES and attenuated the infiltration of CD8 + T cells in nigra. These results indicate the possible involvement of chemokine-dependent adaptive immune response in Parkinsonism. [ABSTRACT FROM AUTHOR]

Immunization of AD mouse models with Aβ reduced Aβ deposits and improved memory and learning deficits, but some clinical trials of immunization with Aβ were halted due to brain inflammation which was presumably induced by a T cell-mediated autoimmune response. We have developed a “possibly safer” vaccine. Our results demonstrate that pcDNA3.1 vector encoding ten repeats of Aβ3-10 fragments elicited high titers of antibodies which reacted well with not only monomeric but also oligomeric and fibrillar forms of Aβ42 peptide. Induced antibodies strongly reacted with amyloid plaques in the brain, demonstrating functional activity of the antibodies. Immunohistochemical and immunofluorescence showed there was significantly less plaque deposition accomplied with less microglia activation as detected both in the frontal cortex and hippocampus. These data suggested that microglial activation is necessary for efficient removal of compact amyloid deposits with immunotherapy. No obvious inflammation T cell and Prussian blue positive cell was found indicated that inflammation T cell infiltration and microhemmorage can be avoided or at least reduced to the minimum level. [ABSTRACT FROM AUTHOR]

Abstract: CGRP significantly stimulated migration of non-activated and anti-CD3 activated T lymphocytes into a collagen matrix when present inside the collagen, whereas somatostatin-14, NPY, substance P, VIP, β-endorphin and metenkephalin had no or little effect. The CGRP antagonist CGRP 8–37 abrogated the CGRP-induced cell infiltration. Virtually all migrating cells were CD3+ (>96%) and CGRP did not stimulate B-cell migration. The migration capacity showed no selective relationship to the expression of CD4+, CD8+, CD45RO+ (memory), or CD45RA+ (naive) T cell markers indicating that the regulation of T cell migration is distinct from that of the major T cell phenotypes. [Copyright &y& Elsevier]

Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy. • dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β • Knockout of cGAS or STING in dMLH tumor cells renders resistance to checkpoint blockade • Downregulating cGAS-STING in human dMLH1 cancers impairs checkpoint blockade therapy About 50% of patients with dMMR cancers are objectively responsive to immunotherapy. In addition to neoantigens, Lu et al. find that dMMR-mediated cytosolic DNA sensing by cGAS-STING pathway in tumor cells contributes to such clinical benefits, while impaired expression of cGAS-STING pathway is associated with drug resistance. [ABSTRACT FROM AUTHOR]