Rectal adenocarcinoma (READ) involves the dysregulated expression of alpha 2,8-Sialyltransferase1 (ST8Sia1) although its role during READ's progression is unclear.

The mRNA level of ST8Sia1 was analyzed based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Tumor Immune Estimation Resource (TIMER) 2.0. Furthermore, the prognostic and significance of ST8Sia1 in READ was assessed through Kaplan-Meier curve, univariate, multivariate Cox regression, and receiver operating characteristic (ROC) methods. The role of ST8Sia1 in the READ immune microenvironment was explored using ESTIMATE analysis and TIMER databases. Furthermore, the expression of ST8Sia1 in tissues was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR), western blotting (WB), and immunohistochemistry (IHC). Perforin and Granzyme B secretion by CD8+ T cells, as well as tumor cell apoptosis, were detected after co-culturing CD8+ T cells with READ tumor cells and ST8Sia1-overexpression (ST8Sia1-OE) tumor cells. Furthermore, we examined the interaction between ST8Sia1 and TGF-β1 in READ cells.

ST8Sia1 exhibited excellent diagnostic capability for READ, with positive correlations to immune response and negative correlations to tumor purity. Increased levels of perforin and Granzyme B from CD8+ T cells were observed in vitro, enhancing tumor cell apoptosis. ST8Sia1 interacts with TGF-β1, mediating its inhibitory effects on READ development.

ST8Sia1 is a potential diagnostic biomarker and therapeutic target for READ, enhancing CD8+ T cell function and possibly improving patient outcomes through cellular immunotherapy.

Tissue-resident memory (TRM) T cells have emerged as key players in cancer immunosurveillance, and their presence has been linked to a favorable clinical outcome in solid cancer patients. Liver metastases exhibit a highly immunosuppressive tumor microenvironment, however, the role and clinical impact of TRM cell infiltration in colorectal cancer remain elusive. The expression of several tissue residency and activation biomarkers has been investigated on tumor-infiltrating lymphocytes isolated from 26 patients' colorectal cancer liver metastases (CRC liver metastases) and compared to 16 peripheral blood samples of patients with CRC liver metastases. Cytokine production was also evaluated in in vitro-activated TRM and non-TRM cells. The prognostic value of TRM cells was also assessed in a well-defined cohort of CRC liver metastases. Here we identified two subsets of TRM cells expressing CD103 and/or CD69 showing significantly higher expression of tissue residency and activation biomarkers. CD103+CD69+ TRM cells subset showed almost exclusive expression of tumor reactivity biomarkers PD-1 and CD39. Supporting this observation, CD103+CD69+ TRM cells showed a more oligoclonal TCR repertoire. Both TRM subsets presented higher cytotoxic and functional capacity compared to non-TRM cells. Our study shows that only the presence of CD103+CD69+ TRM cells is associated with longer recurrence-free survival of colorectal cancer patients with liver metastases. Taken together, our work demonstrates the existence of a phenotypic heterogeneity of TRM cells in colorectal cancer liver metastases. In this study, we identified a population of CD103+CD69+ TRM cells exhibiting the characteristics of tumor reactivity and correlated with better patients' prognosis, with potential implications in optimal therapeutic strategies determination.

Tissue-resident memory T cells (TRMs) reside in peripheral tissues and provide rapid immune defence against local infection and tumours. Tumour-associated TRMs share common tissue-resident features and formation mechanisms, representing some unique subsets of tumour-infiltrating lymphocytes (TILs). However, differences in the tumour microenvironment(TME) and tumour evolution stage result in TRMs exhibiting temporal and spatial heterogeneity of phenotype and function not only at different stages, before and after treatment, but also between tumours originating from different tissues, primary and metastatic cancer, and tumour and adjacent normal tissue. The infiltration of TRMs is often associated with immunotherapy response and favourable prognosis; however, due to different definitions, it has been shown that some subtypes of TRMs can also have a negative impact. Therefore, it is crucial to precisely characterise the TRM subpopulations that can influence the therapeutic efficacy and clinical prognosis of various solid tumours. Here, we review the spatiotemporal heterogeneity of tumour-associated TRMs, as well as the differences in their impact on clinical outcomes. We also explore the relationship between TRMs and immune checkpoint blockade (ICB) and TIL therapy, providing insights into potential new targets and strategies for immunotherapy.

Tissue-resident memory T (TRM) cells are a recently defined subtype of non-recirculating memory T cells with longevity and protective functions in peripheral tissues. As an essential frontline defense against infections, TRM cells have been reported to robustly patrol the tissue microenvironment in malignancies. Accumulating evidence also implicates that TRM cells in the relapse of chronic inflammatory skin diseases such as psoriasis and vitiligo. In light of these developments, this review aims to synthesize these recent findings to enhance our understanding of TRM cell characteristics and actions. Therefore, after providing a brief overview of the general features of the TRM cells, including precursors, homing, retention, and maintenance, we discuss recent insights gained into their heterogeneous functions in skin diseases. Specifically, we explore their involvement in conditions such as psoriasis, vitiligo, fixed drug eruption - dermatological manifestations of drug reactions at the same spot, cutaneous T cell lymphoma, and melanoma. By integrating these diverse perspectives, this review develops a comprehensive model of TRM cell behavior in various skin-related pathologies. In conclusion, our review emphasizes that deciphering the characteristics and mechanisms of TRM cell actions holds potential not only for discovering methods to slow cancer growth but also for reducing the frequency of recurrent chronic inflammation in skin tissue.

Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.

Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8+ T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10Rhi state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy's dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.

The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.

CD8 T cells play a critical role in antitumor immunity. However, over time, they often become dysfunctional or exhausted and ultimately fail to control tumor growth. To effectively harness CD8 T cells for cancer immunotherapy, a detailed understanding of the mechanisms that govern their differentiation and function is crucial. This review summarizes our current knowledge of the molecular pathways that regulate CD8 T cell heterogeneity and function in chronic infection and cancer and outlines how T cells respond to therapeutic checkpoint blockade. We explore how T cell-intrinsic and -extrinsic factors influence CD8 T cell differentiation, fate choices, and functional states and ultimately dictate their response to therapy. Identifying cells that orchestrate long-term antitumor immunity and understanding the mechanisms that govern their development and persistence are critical steps toward improving cancer immunotherapy.

Improving pathological complete response (pCR) rate is currently the main goal of neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (LA-ESCC). However, improved pCR rates do not consistently translate into better prognosis, likely due to regimen-specific pCR heterogeneity. We investigated this heterogeneity and potential biomarkers between two common neoadjuvant regimens.

We included 445 LA-ESCC patients from four centers, with 228 receiving neoadjuvant chemoradiotherapy (nCRT) and 217 undergoing neoadjuvant chemotherapy combined with immunotherapy (nICT). Propensity score matching ensured group comparability. We assessed pCR rates and their associations with overall survival (OS), disease-free survival (DFS), and recurrence patterns. Immune-related biomarkers were investigated through RNA sequencing and immune infiltration analysis, then validated via multiplex immunofluorescence staining.

Overall, pCR was associated with significantly higher DFS (HR = 0.3 [0.18-0.5], P < 0.01) and OS (HR = 0.19 [0.08-0.41], P < 0.01) compared to non-pCR. The nICT group had a lower pCR rate than the nCRT group (27.2% vs. 42.9%) but demonstrated comparable prognosis and reduced distant metastasis. Among pCR patients, DFS was significantly better in the nICT group (HR = 0.2 [0.05-0.86], P = 0.031), with a trend toward improved OS. Immune analysis revealed increased CD8 + T cell infiltration, particularly CD69 + CD8 + tissue-resident memory T cells (TRM), in the nICT pCR group. The proportion of CD69 + CD8 + TRM cells was significantly linked to improved DFS (P = 0.016) and OS (P = 0.015), suggesting they may be superior prognostic markers compared to pCR rates.

The pCR obtained from different neoadjuvant treatments has distinct prognostic outcomes. The CD69 + CD8 + TRM, as a potential prognostic predictor, warrants further investigation.

Tissue resident memory CD8+ T cells (Trm) constitute a distinct population of non-circulating memory T cells1-5 vastly exceeding the number of circulating T cells5, and play a pivotal role in protective immunity against pathogens6-8. How to promote the generation of vaccine specific Trm remains an important challenge. Whether Trm contribute also to immune control of tumors or just correlate with an unrelated process linked to clinical outcome has not been unequivocally established9,10, and phenotypic markers such as co-expression of CD69 and CD103 or CD49a integrins commonly used to monitor tumor infiltrating Trm do not unambiguously define this subset. Here we tested the hypothesis that transient downregulation of KLF2, the most conserved feature of Trm ontogeny4,11,12, will promote the differentiation of vaccine activated CD8+ T cells into Trm and enhance antitumor immunity. We show that 4-1BB antibody targeted delivery of a KLF2 siRNA to tumor bearing mice led to the downregulation of KLF2 in vaccine activated CD8+ T cells and the accumulation of phenotypically defined intratumoral CD69+CD103+ and CD69+CD49a+ CD8+ T cells which correlated with enhanced control of tumor growth. This study could serve as the foundation of a broadly applicable and clinically useful way to promote the generation of vaccine specific Trm and provides direct evidence that intratumoral CD8+CD69+CD103+ and CD8+CD69+CD49a+ cells are indeed Trm and that Trm contribute to tumor immunity.

To investigate the function of mitophagy in instructing T-cell differentiation of patients with rheumatoid arthritis (RA).

The mRNA and protein levels of optic atrophy protein-1 were detected in T cells from 94 RA patients and 37 age- and sex-matched healthy individuals by quantitative polymerase chain reaction and Western blotting. The impact of mitophagy on the differentiation of T cells was determined by flow cytometry. The therapeutic effect of targeting mitophagy was explored in humanized RA chimeras.

Our study showed that T cells exerted high levels of mitophagy in RA patients. Since multiple T-cell subtypes play crucial roles in RA, we determined that mitophagy had a significant impact on the differentiation of tissue-resident memory T (Trm) cells, but not Th1 or Th17 cells. Importantly, we demonstrated that inhibiting mitophagy significantly reduced the number of Trm cells and downregulated inflammatory responses, as evidenced by diminished levels of T cell receptor β, interferon-γ, and interleukin-17A, in the humanized RA chimeras.

Mitophagy is elevated in RA T cells, leading to maldifferentiation of Trm cells in RA patients. Since these findings were obtained from clinical patients, mitophagy may be a potential therapeutic target for RA treatment.

Anaerobic bacteriolytic cancer therapy, whether delivered locally or systemically, frequently encounters challenges related to limited colonization within hypoxic pockets of central tumors and activation of innate immunity. Herein we have developed trans-arterial bacteria embolization therapy using bacterial embolic microspheres. C. novyi-NT spores loaded calcium alginate embolic microspheres demonstrated C. novyi-NT metabolites-mediated microsphere degradation, releasing vegetative C. novyi-NT bacterial in hypoxic condition. Transcatheter directed bacterial microsphere embolization therapy occludes tumor feeding vessels with infused bacterial embolic microspheres and enhances tumoral hypoxia. Notably, anaerobic bacterial metabolism responsive microsphere-bacterial embolization therapy achieved a complete tumor response with enhanced tumor-specific bacterial delivery and colonization, resulting in cancer cell killing across the entire tumor. In vivo tumor response and immunological profiling revealed that bacterial embolization uniquely enhances anti-cancer response, effectively engaging direct anaerobic bacterial oncolysis and adaptive and innate immune responses in a cooperative manner.

Strategically targeting lymph nodes (LNs) to orchestrate the initiation and regulation of adaptive immune responses is one of the most pressing challenges in the context of vaccination. Herein, a series of polymer-TLR agonist conjugates (PTACs) is developed to investigate the impact of dendritic-topological characteristics on their LN targeting activity in vivo, and their molecular weight (MW) on their pharmacokinetics in support of their LN homing. Notably, the dendritic 6-arm PTAC with a MW of 60 kDa (6A-PTAC-60k) rapidly delivered cargo to draining LNs after administration to peripheral tissues. Specifically, this topologic structure ameliorated the targeting behavior within lymphatic vessels and LNs, including an elevated amount of TLR7/8 agonist delivered to the LNs, an improved distribution pattern among barrier cells and immune cells, increased permeability, and prolonged retention. Furthermore, the 6A-PTAC-60k formulation induced broad antibody and T cell responses, enhancing vaccine immunogenicity and suppressing tumor growth. The results revealed that both the topology and MW of polymers are crucial factors for immunoadjuvant distribution and their functional activity in the draining LNs, which, in turn, enhanced the immunogenicity of the vaccine formulation. This study may provide a chemical and structural basis for optimizing the design of immunoadjuvant delivery systems.

Tissue-resident memory T (TRM) cells are a specialized subset of memory T cells that permanently reside in non-lymphoid tissues, providing localized and long-lasting immune protection. In the urinary tract, TRM cells play critical roles in defending against infections, mediating tumor immunity, and influencing the pathogenesis of chronic inflammatory diseases. Their therapeutic potential is immense, with promising avenues for vaccine development, enhanced cancer immunotherapy, and targeted treatments for chronic inflammation. However, challenges remain in harnessing their protective roles while minimizing their pathological effects, particularly in immunosuppressive or inflammatory microenvironments. This review explores the diverse roles of TRM cells in urinary tract diseases, including infections, cancer, and chronic inflammation, and discusses therapeutic strategies and future directions for leveraging TRM cells to improve clinical outcomes. By advancing our understanding of TRM cell biology, we can develop innovative interventions that balance their immune-protective and regulatory functions.

In many solid tumours, including gastric cancer (GC), the beginning and progression of the tumour are closely correlated with the tumour microbiome. Here, we show the changes in the gastric microbiota and their influence on immune regulation and the promotion of GC progression through 16s rRNA sequencing and single cell RNA sequencing. Streptococcus lutetiensis (S. lutetiensis) was found to be enriched in the tumour tissues of GC patients. Further analysis using single-cell sequencing and flow cytometry showed that S. lutetiensis notably affects the antitumour immunity by suppressing IL17 signalling and reducing the population of CD8+IL17A+ tissue-resident memory T (TRM) cells by activating Nrf2-mediated oxidative stress response. Mouse models confirm S. lutetiensis promotes GC progression by impairing immune responses in CD8+IL17A+TRM cells, suggesting it as a potential GC prognosis indicator and immunotherapy target, highlighting the microbiome's role in cancer progression.

Lung adenocarcinoma (LUAD) is a very common and lethal kind of lung malignancy. An increasing number of studies indicated that tissue-resident memory T (TRM) cells played significant roles in anti-cancer immunity. In our previous study, EXO1 was found to be a core gene for TRM cells in the prognosis of LUAD. However, the roles of EXO1 in the tumor microenvironment, and its application in the diagnosis and prognosis prediction of LUAD are still inadequately explored. In this study, the RNA expression, DNA methylation, CNV, somatic mutation data of EXO1, and the corresponding patients' clinical information from publicly available databases were analyzed using bioinformatic methods. The results were validated through immunohistochemical staining of EXO1 in LUAD samples. The results showed EXO1 was aberrantly highly expressed in LUAD tissues. High expression of EXO1 was a risky factor for LUAD patients. The expression level of EXO1 was associated with many clinical features such as TNM stages. It can also distinguish normal tissues and LUAD tumor tissues accurately. EXO1 expression was correlated with the infiltration of immune cells, and high expression of EXO1 was an adverse effect on LUAD patients receiving anti-PD-1/PD-L1 immunotherapy. Moreover, patients with EXO1 mutation had worse DSS, DFI and PFI.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis and lack of effective treatments. In recent years, peptide vaccines that use sequences based on tumor-specific or tumor-associated antigens to activate immune responses against tumor cells have emerged as a new therapeutic strategy. In this study, we developed a novel therapeutic polypeptide vaccine targeting the tumor-associated antigen Fibrinogen-Like Protein 2 (FGL2), whose dominant epitope peptide was tandemly linked to the C-terminus of HCMV-IE1mut via a linker. We used this vaccine to compare the therapeutic efficacy of HCMV-IE1mut alone versus HCMV-IE1mut-FGL2172-220 and investigate the potential mechanism of action of HCMV-IE1mut-FGL2172-220 in glioma treatment. An in situ GBM model (GL261-IE1-luc cells) was used to determine the efficacy of the vaccine. Treatment with HCMV-IE1mut-FGL2172-220 exerted antitumor effects and extended the survival of the GL261 animal model. We observed reduced proportions of microglia, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) by immunofluorescence. Flow cytometry showed that compared to HCMV-IE1mut alone, treatment with HCMV-IE1mut-FGL2172-220 increased the proportion of CD8+ T cells and tissue-resident memory T cells (TRM). ELISA analysis showed that it improved the secretion of tumor-specific IFN-γ and TNF-α by these cells and downregulated the expression of IL-6 and IL-10. Our study demonstrates that the long-peptide FGL2172-220 improves the antitumor efficacy of HCMV-IE1mut, possibly by reshaping immune cells in the glioma microenvironment. These findings lay the groundwork for the development of therapeutic antigenic peptide vaccines to improve antitumor effects for cancer.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite advancements in therapeutic methodologies, it still causes a high rate of patient mortality. CD8+ tissue-resident memory T (TRM) cells are strategically positioned to mediate effective anti-tumor responses. However, the characteristic surface molecules and functions of CD8+ TRM cells exhibit significant heterogeneity.

The roles and anti-tumor biological functions of different CD8+ TRM subsets in CRC were determined by clinical CRC samples, bioinformatics analysis, and in vitro experiments including co-culture experiments and transwell migration assays. The signaling pathways that synergistically regulate the differentiation of CD8+ TRM cells were identified by in vitro CD8+ T cell activation and inhibition assays, and the functioning transcription factors were predicted using the UCSC and JASPAR databases.

We found that different CD8+ TRM subsets existed in CRC tumor tissues, which were identified as CD69-CD103-CD8+ TRM, CD69+CD103-CD8+ TRM (SP CD8+ TRM), and CD69+CD103+CD8+ TRM (DP CD8+ TRM) subsets. Compared with SP CD8+ TRM cells, increased infiltration of DP CD8+ TRM cells predicted better prognosis and played a protective role mainly in tumor invasion and lymph node metastasis of CRC. DP CD8+ TRM cells expressed higher levels of effector molecules and exerted stronger anti-tumor effects in a FAS/FASL pathway-dependent manner. Additionally, DP CD8+ TRM cells secreted higher levels of CXCL13 and recruited B cells into tumor tissues through the CXCL13/CXCR5 signaling axis to form tertiary lymphoid structures, participating in anti-tumor immune responses. Notch and TGF-β signaling pathways synergistically regulate the differentiation of DP CD8+ TRM cells.

We clarified the roles and mechanisms of different CD8+ TRM subsets in CRC and identified that DP CD8+ TRM cells exert stronger anti-tumor effects and predict better prognosis, which provides ideas for developing new clinically available therapeutic targets.

Tissue-resident memory T (TRM) cells preferentially reside in peripheral tissues, serving as key players in tumor immunity and immunotherapy. The lack of effective approaches for expanding TRM cells and delivering these cells in vivo hinders the exploration of TRM cell-mediated cancer immunotherapy. Here, we report a nanoparticle artificial antigen-presenting cell (nano-aAPC) ex vivo expansion approach and an in vivo delivery system for TRM cells. Using the nano-aAPC platform, we expanded functional antigen-specific murine and human TRM-like CD8+ T cells ex vivo. We also developed an injectable macroporous hyaluronic acid (HA) hydrogel to deliver TRM-like cells. TRM-like cells delivered in the optimized HA hydrogel trigger robust local and systemic antitumor immunity and show synergistic effects with anti-PD-1 treatment. Our findings suggest that nano-aAPC-induced TRM-like cells, coupled with a hydrogel delivery system, offer an efficient way to advance the understanding of TRM cell-mediated cancer therapy.

Hyperprogressive disease can occur in cancer patients receiving immune checkpoint blockade (ICB) therapy, but whether and how reactive cytotoxic T lymphocytes (CTLs) exert protumorigenic effects in this context remain elusive. Herein, our study reveals that pericancerous macrophages cross-present antigens to CD103+ CTLs in hepatocellular carcinoma (HCC) via the endoplasmic reticulum (ER)-associated degradation machinery-mediated cytosolic pathway. This process leads to the retention of CD103+ CTLs in the pericancerous area, whereby they activate NLRP3 inflammasome in macrophages, promoting hepatoma progression and resistance to immunotherapy. Our single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analysis of HCC patients shows that despite their tissue-resident effector phenotype, the aggregation of CD103+ CTLs predicts unfavorable clinical outcomes for HCC patients receiving multiple types of treatment. Correspondingly, therapeutic strategies that redistribute CD103+ CTLs can disrupt this pathogenic interplay with macrophages, enhancing the efficacy of ICB treatment against HCC.

Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.

Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (TRM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8+ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8+ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated TRM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8+ T cells by restoring TRM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8+ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced TRM restriction as a key mechanism causing aged CD8+ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.

The respiratory tract is susceptible to various infections and can be affected by many serious diseases. Vaccination is one of the most promising ways that prevent infectious diseases and treatment of some diseases such as malignancy. Direct delivery of vaccines to the respiratory tract could mimic the natural process of infection and shorten the delivery path, therefore unique mucosal immunity at the first line might be induced and the efficiency of delivery can be high. Despite considerable attempts at the development of respiratory vaccines, the rational formulation design still warrants attention, i.e., how the formulation composition, particle properties, formulation type (liquid or solid), and devices would influence the immune outcome. This article reviews the recent advances in the formulation design and development of respiratory vaccines. The focus is on the state of the art of delivering antigenic compounds through the respiratory tract, overcoming the pulmonary bio-barriers, enhancing delivery efficiencies of respiratory vaccines as well as maintaining the stability of vaccines during storage and use. The choice of devices and the influence of deposition sites on vaccine efficiencies were also reviewed.

Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that whereas skin TRM cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive TRM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal TRM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated TRM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.

The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis inhibits T cell activity, impairing anti-tumor immunity. Blocking this axis with therapeutic antibodies is one of the most promising anti-tumor immunotherapies. It has long been recognized that PD-1/PD-L1 blockade reinvigorates exhausted T (TEX) cells already present in the tumor microenvironment (TME). However, recent advancements in high-throughput gene sequencing and bioinformatic tools have provided researchers with a more granular and dynamic insight into PD-1/PD-L1 blockade-responding cells, extending beyond the TME and TEX populations. This review provides an update on the cell identity, spatial distribution, and treatment-induced spatiotemporal dynamics of PD-1/PD-L1 blockade responders. It also provides a synopsis of preliminary reports of potential PD-1/PD-L1 blockade responders other than T cells to depict a panoramic picture. Important questions to answer in further studies and the translational and clinical potential of the evolving understandings are also discussed.

Immunotherapy has revolutionized the treatment paradigm for hepatocellular carcinoma (HCC). However, its efficacy varies significantly with each patient's genetic composition and the complex interactions with their microbiome, both of which are pivotal in shaping anti-tumor immunity. The emergence of microbial neoantigens, a novel class of tumor vaccines, heralds a transformative shift in HCC therapy. This review explores the untapped potential of microbial neoantigens as innovative tumor vaccines, poised to redefine current HCC treatment modalities. For instance, neoantigens derived from the microbiome have demonstrated the capacity to enhance anti-tumor immunity in colorectal cancer, suggesting similar applications in HCC. By harnessing these unique neoantigens, we propose a framework for a personalized immunotherapeutic response, aiming to deliver a more precise and potent treatment strategy for HCC. Leveraging these neoantigens could significantly advance personalized medicine, potentially revolutionizing patient outcomes in HCC therapy.

Therapeutic resistance is a main obstacle to achieve long-term benefits from immune checkpoint inhibitors. The underlying mechanism of neoadjuvant anti-PD-1 resistance remains unclear.

Multi-omics analysis, including mass cytometry, single-cell RNA-seq, bulk RNA-seq, and polychromatic flow cytometry, was conducted using the resected tumor samples in a cohort of non-small cell lung cancer (NSCLC) patients received neoadjuvant anti-PD-1 therapy. Tumor and paired lung samples acquired from treatment-naïve patients were used as a control. In vitro experiments were conducted using primary cells isolated from fresh tissues and lung cancer cell lines. A Lewis-bearing mouse model was used in the in vivo experiment.

The quantity, differentiation status, and clonal expansion of tissue-resident memory CD8+ T cells (CD8+ TRMs) are positively correlated with therapeutic efficacy of neoadjuvant anti-PD-1 therapy in human NSCLC. In contrast, the quantity of immature CD1c+ classical type 2 dendritic cells (imcDC2) and galectin-9+ cancer cells is negatively correlated with therapeutic efficacy. An epithelium/imDC2 suppressive axis that restrains the antitumor response of CD8+ TRMs via galectin-9/TIM-3 was uncovered. The expression level of CD8+ TRMs and galectin-9+ cancer cell-related genes predict the clinical outcome of anti-PD-1 neoadjuvant therapy in human NSCLC patients. Finally, blockade of TIM-3 and PD-1 could improve the survival of tumor-bearing mouse by promoting the antigen presentation of imcDC2 and CD8+ TRMs-mediated tumor-killing.

Galectin-9 expressing tumor cells sustained the primary resistance of neoadjuvant anti-PD-1 therapy in NSCLC through galectin-9/TIM-3-mediated suppression of imcDC2 and CD8+ TRMs. Supplement of anti-TIM-3 could break the epithelium/imcDC2/CD8+ TRMs suppressive loop to overcome anti-PD-1 resistance.

NCT03732664.

Tissue-resident memory T cells (TRMs) play a critical role in cancer immunity by offering quick and effective immune responses. However, the cellular heterogeneity of TRMs and their significance in cervical cancer (CC) remain unknown. In this study, we generated and analyzed single-cell RNA sequencing data from 12,945 TRMs (ITGAE+ CD3D+) and 25,627 non-TRMs (ITGAE- CD3D+), derived from 11 CC tissues and 5 normal cervical tissues. We found that TRMs were more immunoreactive than non-TRMs, and TRMs in CC tissues were more activated than those in normal cervical tissues. Six CD8+ TRM subclusters and one CD4+ TRM subcluster were identified. Among them, CXCL13+ CD8+ TRMs were more abundant in CC tissues than in normal cervical tissues, had both cytotoxic and inhibitory features, and were enriched in pathways related to defense responses to the virus. Meanwhile, PLAC8+ CD8+ TRMs were less abundant in CC tissues than in normal cervical tissues but had highly cytotoxic features. The signature gene set scores of both cell subclusters were positively correlated with the overall survival and progression-free survival of patients with CC following radiotherapy. Of note, the association between HLA-E and NKG2A, either alone or in a complex with CD94, was enriched in CXCL13+ CD8+ TRMs interacting with epithelial cells at CC tissues. The in-depth characterization of TRMs heterogeneity in the microenvironment of CC could have important implications for advancing treatment and improving the prognosis of patients with CC.

Tissue-resident memory T cells (TRM) are a specialized subset of T cells that reside in tissues and provide long-term protective immunity against pathogens that enter the body through that specific tissue. TRM cells have specific phenotype and reside preferentially in barrier tissues. Recent studies have revealed that TRM cells are the main target of immune checkpoint inhibitor immunotherapy since their role in cancer immunosurveillance. Furthermore, TRM cells also play a crucial part in pathogenesis of immune-related adverse events (irAEs). Here, we provide a concise review of biological characteristics of TRM cells, and the major advances and recent findings regarding their involvement in immune checkpoint inhibitor immunotherapy and the corresponding irAEs.

Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint and stimulatory genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification.

Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IShigh malignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells.