Anticancer Immunity Research Articles

Cancer Immunotherapy Using Bioengineered Micro/Nano Structured Hydrogels.

Hydrogels, a class of materials with a 3Dnetwork structure, are widely used in various applications of therapeutic delivery, particularly cancer therapy. Micro and nanogels as miniaturized structures of the bioengineered hydrogels may provide extensive benefits over the common hydrogels in encapsulation and controlled release of small molecular drugs, macromolecular therapeutics, and even cells. Cancer immunotherapy is rapidly developing, and micro/nanostructured hydrogels have gained wide attention regarding their engineered payload release properties that enhance systemic anticancer immunity. Additionally, they are a great candidate due to their local administration properties with a focus on local immune cell manipulation in favor of active and passive immunotherapies. Although applied locally, such micro/nanostructured can also activate systemic antitumor immune responses by releasing nanovaccines safely and effectively inhibiting tumor metastasis and recurrence. However, such hydrogels are mostly used as locally administered carriers to stimulate the immune cells by releasing tumor lysate, drugs, or nanovaccines. In this review, the latest developments in cancer immunotherapy are summarized using micro/nanostructured hydrogels with a particular emphasis on their function depending on the administration route. Moreover, the potential for clinical translation of these hydrogel-based cancer immunotherapies is also discussed.

Glutamine availability unleashes dendritic cells’ anti-tumor power

Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo etal.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.

Tracing anti-cancer immunity in patients undergoing liver transplantation for HCC after downstaging with immunotherapy

Tracing anti-cancer immunity in patients undergoing liver transplantation for HCC after downstaging with immunotherapy

Escherichia coli adhesion portion FimH polarizes M2 macrophages to M1 macrophages in tumor microenvironment via toll-like receptor 4.

Macrophages are key effector cells of innate immunity and play a critical role in the immune balance of disease pathogenesis, especially in the tumor microenvironment. In previous studies, we showed that FimH, an Escherichia coli adhesion portion, promoted dendritic cell activation. However, the effect of FimH in macrophage polarization has yet to be fully examined. In this study, we investigated the potential effect of FimH on macrophages, as well as the polarization from M2 to M1 macrophages, contributing to the overall antitumor effect. Mouse bone marrow derived macrophages and peritoneal macrophages were generated to test the effect of FimH in vitro. The expression of costimulatory molecules and production of cytokines were analyzed. The effect of FimH in the tumor-associated macrophages was examine in the B16F10-tumor bearing C57BL/6. FimH was found to promote M1 macrophage activation. In addition, FimH polarized M2 macrophages, which were induced by interleukin (IL)-4 and IL-13 into M1 macrophages were dependent on toll-like receptor 4 and myeloid differentiation factor 2. Moreover, FimH reprogramed the tumor-associated macrophage (TAM) into M1 macrophages in B16 melanoma tumor-bearing mice and promoted an inflammatory reaction in the tumor microenvironment (TME). Furthermore, FimH promoted M1 macrophage activation, as well as the reversion of M2 macrophages into M1 macrophages in humans. Finally, FimH treatment was found to enhance the anti-cancer immunity of anti-PD-L1 antibody by the induction of M1 polarization from TAM. This study demonstrated the potential effect of FimH on the activation of macrophages, responsible for the repolarization of M2 macrophages into the M1 phenotype via the TLR4 signaling pathway. Moreover, FimH could also reprogram TAM polarization to the M1 status in the TME, as well as enhance the anti-tumor activity of immune checkpoint blockade.

248. SYSTEMIC INFLAMMATORY MARKERS AS PROGNOSTIC FACTORS IN ESOPHAGEAL CANCER: A MEXICAN PERSPECTIVE

Abstract Background Esophageal cancer (EC) represents the eighth most commonly diagnosed cancer, and sixth cause of cancer-related deaths worldwide. Several studies have demonstrated an association between systemic inflammation, anti-cancer immunity, and poor oncological outcomes in patients with EC. Biomarkers including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) may reflect the balance between pro-cancer inflammation and anti-cancer immune response and have prognostic implications in Mexican esophageal cancer patients. Methods A retrospective review of a prospectively collected database of all EC patients from 2011–2022 was performed. Baseline pre-treatment NLR, LMR and PLR was collected. The date of last follow-up or death was ascertained from medical records. ROC curves were used to calculate cut-off values for NLR and PLR, while the median-value was used for LMR. Serum albumin of <3.5 g/dL was considered malnutrition. Kaplan–Meier (univariate) and Cox regression (multivariate) were performed to evaluate survival against prognostic factors. Results 498 patients were included during the study period, 80.1% men and 19.9% women, median age 60 (±12.2) years old. Adenocarcinoma (49.8%) was the most common histological subtype, followed by squamous cell carcinoma (31.7%). Clinical stage included: I (3%), IIA-B (11.8%), III (37.6%), IVA (2.6%), and IVB (44.2%). Neoadjuvant chemoradiotherapy was the predominant initial therapy (50.4%), followed by chemotherapy (41.7%). ROC curves revealed the following cut-off value: 2.92 for NLR, 174 for IPL, and 3.5 for LMR. In the univariate analysis, four prognostic factors were significant for overall survival (NLR, PLR, LMR, albumin) (Table 1), while in the multivariate analysis only NLR and albumin remained independent factors for survival (Table 2). Conclusion In our population, low NLR and high albumin can be considered independent prognostic markers in patients with esophageal cancer. These common pretreatment biomarkers can serve to identify patients with good prognostic factors, contributing to an improved consent process and therapeutic decision making. Further research should focus on more accurate cut-off values for survival prognostication.

Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control

CD4 Tcells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory Tcells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.

Dendritic polymer-functionalized nanomedicine potentiates immunotherapy via lethal energy crisis-induced PD-L1 degradation

The advent of immune checkpoint inhibitors ushers in a new era of anti-tumor immunity. However, current clinical anti-PD-L1 antibodies only interdict PD-L1 on the membrane, which cannot diminish the complex cancer-promoting effects of intracellular PD-L1. Therefore, directly reducing the PD-L1 abundance of cancer cells might be a potential PD-L1 inhibitory strategy to circumvent the issues of current anti-PD-L1 antibodies. Herein, we develop a dendritic polymer-functionalized nanomedicine with a potent cellular energy depletion effect on colon cancer cells. Treatment with the nanomedicine significantly promotes phosphorylation of AMPK, which in turn leads to PD-L1 degradation and eventual T cell activation. Meanwhile, the nanomedicine can potently induce immunogenic cell death (ICD) to enhance the anti-cancer immunity. Moreover, the combination of the nanomedicine with PD-1 blockade further enhances the activity of cytotoxic T lymphocytes, and dramatically inhibits tumor growth in vivo without distinct side effects. Overall, this study provides a promising nanoplatform to induce lethal energy crisis and ICD, and suppress PD-L1 expression, thus potentiating cancer immunotherapy.

BCL2 Inhibition Reveals a Dendritic Cell-Specific Immune Checkpoint That Controls Tumor Immunosurveillance.

BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.

Protein-rich fraction of Protaetia brevitarsis seulensis larvae induce maturation of dendritic cells and Th1-polarization: A promising adjuvant for anticancer therapy

The objective of this study was to investigate the potential anticancer immunostimulatory properties of a protein-rich fraction obtained from larvae of Protaetia brevitarsis seulensis (PBLP), a highly nutritious edible insect, in CT-26 colon carcinoma-bearing mice. The most abundant essential amino acids (EAA) in PBLP were Val, Ile, and Leu, while the most abundant non-EAA were Pro, Glu, and Gly. PBLP increased the production of Th1-polarized cytokines and the phenotypic maturation of bone marrow-derived dendritic cells (BMDCs). PBLP-treated BMDCs stimulated naïve CD4+ and CD8+ T cells to produce IFN-γ and IL-2 but not IL-5. Significantly, dietary PBLP restored CD86 and MHC-I expression in splenic DCs, and also increased TNF-α+IL-2+IFN-γ+CD107+ polyfunctional CD4+ and CD8+ T cells in the spleen, thereby inhibiting tumor growth in CT-26 tumor-bearing mice. Collectively, PBLP synchronizes DCs and T cells for anticancer immunity, suggesting that it could serve as a potential adjuvant or supplement for cancer treatment.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and theacidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes

ABSTRACT Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.

RAB27B expression in pancreatic cancer is predictive of poor survival but good response to chemotherapy.

Pancreatic cancer is the 4th leading cause of cancer-related death with poor survival even after curative resection. RAB27A and RAB27B are key players in the exosome pathway where they play important roles in exosome secretion. Evidence suggests that RAB27A and RAB27B expression not only leads to tumor proliferation and invasion, but also plays an important role in antigen transfer necessary for anticancer immunity. In this study, we analyze the expression of RAB27A and RAB27B in patients after pancreatic cancer surgery with or without adjuvant chemotherapy and its influence on overall survival. We analyzed a total of 167 patients with pancreatic cancer for their RAB27A and RAB27B expression. We dichotomized the patients along the median and compared survival in patients with high and low RAB27A and RAB27B expression with or without adjuvant chemotherapy treatment. We found a significant improvement in overall survival in patients with a negative resection margin (p= 0.037) and in patients who received adjuvant chemotherapy (p= 0.039). The survival benefit after chemotherapy was dependent on RAB27B expression status: only the subgroup of patients with high RAB27B expression benefited from adjuvant chemotherapy (p= 0.006), but not the subgroup with low RAB27B expression (p= 0.59). Patients with high RAB27B expression who did not receive adjuvant chemotherapy showed a trend towards worse survival compared to the other subgroups. This difference was abolished after treatment with adjuvant chemotherapy. These results suggest that RAB27B expression in pancreatic cancer might identify a subgroup of patients with poor survival who might respond well to adjuvant chemotherapy. If resectable, these patients could be considered for neoadjuvant chemotherapy to minimize the risk of not receiving adjuvant chemotherapy. Further prospective studies are needed to confirm these findings.

Machine learning reveals genetic modifiers of the immune microenvironment of cancer

Heritability in the immune tumor microenvironment (iTME) has been widely observed yet remains largely uncharacterized. Here, we developed a machine learning approach to map iTME modifiers within loci from genome-wide association studies (GWASs) for breast cancer (BrCa) incidence. A random forest model was trained on a positive set of immune-oncology (I-O) targets, and then used to assign I-O target probability scores to 1,362 candidate genes in linkage disequilibrium with 155 BrCa GWAS loci. Cluster analysis of the most probable candidates revealed two subfamilies of genes related to effector functions and adaptive immune responses, suggesting that iTME modifiers impact multiple aspects of anticancer immunity. Two of the top ranking BrCa candidates, LSP1 and TLR1, were orthogonally validated as iTME modifiers using BrCa patient biopsies and comparative mapping studies, respectively. Collectively, these data demonstrate a robust and flexible framework for functionally fine-mapping GWAS risk loci to identify translatable therapeutic targets.

Eph receptor B6 shapes a cold immune microenvironment, inhibiting anti-cancer immunity and immunotherapy response in bladder cancer.

The role of Eph receptors and related ephrin (EFN) ligands (as the largest family of transmembrane-bound RTKs) in immunomodulation in many types of cancer, especially bladder cancer (BLCA), is scarcely known. A pan-cancer dataset was retrieved from The Cancer Genome Atlas (TCGA) to explore the relation between Eph receptor/EFN ligand family genes and immunomodulators and tumor-infiltrated immune cells (TIICs). Local BLCA, GSE32894, and GSE31684 cohorts were applied to validate. The IMvigor210 cohort was employed to explore the relationship between EPHB6 and immunotherapy response. Moreover, association between EPHB6 and molecular subtype was investigated to explore potential therapeutic strategies. Immunohistochemical staining of CD8 and CD68 was performed to validate the correlation between EPHB6 and TIICs. The pan-cancer analysis revealed variations in the immunological effects of Eph receptor/EFN ligand family genes across different types of cancer. EPHB6 expression negatively correlated with the expression of the majority of immunomodulators (including HLA and immune checkpoints), and CD8 T cells and macrophages in both the TCGA-BLCA and validation BLCA cohorts, shaping a cold immune microenvironment with inhibited immunity. In the IMvigor210 cohort, patients with high-EPHB6 highly correlated with a non-inflamed, low PD-L1 expression immune phenotype, and correspondingly, with less responders to immunotherapy. The high-EPHB6 group, enriched with the basal subtype, presented significantly fewer TP53 and more FGFR3 genomic alterations. Finally, a novel EPHB6-related Genes signature, with reliable and robust ability in prognosis prediction, was constructed. This study comprehensively investigated the immunological effects of Eph receptor/EFN ligand family genes pan-cancer, and specially identified the immunosuppressive role of EPHB6 in BLCA. Furthermore, EPHB6 may predict the molecular subtype and prognosis of BLCA, and serve as a novel therapeutic target to improve the sensitivity of immunotherapy.

Dietary intervention in enhancing immunity of cancer patients

The compromised function and environment of the immune system in individuals with cancer create a scenario in which the immune system fails to effectively identify and eliminate cancer cells. As a result, tumors can thrive and avoid detection by the immune system, leading to the progression of the disease. Gaining a comprehensive understanding of these immune-related challenges is essential for the development of effective cancer treatments, including immunotherapies, which aim to enhance the immune response against cancer. In addition to conventional treatments, dietary interventions have shown potential in supporting cancer patients by improving their immune function through nutritional support, influencing the gut microbiome, boosting the immune system, and other means. It is crucial to note that these dietary interventions should be tailored to each individual cancer patient, considering their specific requirements, preferences, and tolerances. This review seeks to underscore the significance of implementing well-adapted and appropriate dietary approaches to enhance the anticancer immunity of cancer patients.

Take my breath away: TAM-ing anti-cancer immunity in hypoxic niches

Hypoxia is a major driver of tumor aggressiveness and therapy resistance in GBM. In this issue of Immunity, Sattiraju etal. functionally link hypoxia with diminished anti-cancer immunity caused by sequestration of immunosuppressive TAMs and CTLs in pseudopalisades in GBM.

A distinct stimulatory cDC1 subpopulation amplifies CD8+ Tcell responses in tumors for protective anti-cancer immunity.

Type 1 conventional dendritic cells (cDC1) can support Tcell responses within tumors but whether this determines protective versus ineffective anti-cancer immunity is poorly understood. Here, we use imaging-based deep learning to identify intratumoral cDC1-CD8+ Tcell clustering as a unique feature of protective anti-cancer immunity. These clusters form selectively in stromal tumor regions and constitute niches in which cDC1 activate TCF1+ stem-like CD8+ Tcells. We identify a distinct population of immunostimulatory CCR7neg cDC1 that produce CXCL9 to promote cluster formation and cross-present tumor antigens within these niches, which is required for intratumoral CD8+ Tcell differentiation and expansion and promotes cancer immune control. Similarly, in human cancers, CCR7neg cDC1 interact with CD8+ Tcells in clusters and are associated with patient survival. Our findings reveal an intratumoral phase of the anti-cancer Tcell response orchestrated by tumor-residing cDC1 that determines protective versus ineffective immunity and could be exploited for cancer therapy.

Identification of INHBA as a potential biomarker for gastric cancer through a comprehensive analysis

Inhibin subunit beta A (INHBA) is a member of the transforming growth factor-beta (TGF-β) superfamily that plays a fundamental role in various cancers. However, a systematic analysis of the exact role of INHBA in patients with gastric cancer (GC) has not yet been conducted. We evaluated the expression levels of INHBA and the correlation between INHBA and GC prognosis in GC. The relationship between INHBA expression, immune infiltration levels, and type markers of immune cells in GC was also explored. In addition, we studied INHBA mutations, promoter methylation, and functional enrichment analysis. Besides, high expression levels of INHBA in GC were significantly related to unfavorable prognosis. INHBA was negatively correlated with B cell infiltration, but positively correlated with macrophage and most anticancer immunity steps. INHBA expression was positively correlated with the type markers of CD8+ T cells, neutrophils, macrophages, and dendritic cells. INHBA has a weak significant methylation level change between tumor and normal tissues and mainly enriched in cancer-related signaling pathways. The present study implies that INHBA may serve as a potential biomarker for predicting the prognosis of patients with GC. INHBA is a promising predictor of immunotherapy response, with higher levels of INHBA indicating greater sensitivity.

Reovirus combined with a STING agonist enhances anti-tumor immunity in a mouse model of colorectal cancer.

Reovirus, a naturally occurring oncolytic virus, initiates the lysis of tumor cells while simultaneously releasing tumor antigens or proapoptotic cytokines in the tumor microenvironment to augment anticancer immunity. However, reovirus has developed a strategy to evade antiviral immunity via its inhibitory effect on interferon production, which negatively affects the induction of antitumor immune responses. The mammalian adaptor protein Stimulator of Interferon Genes (STING) was identified as a key regulator that orchestrates immune responses by sensing cytosolic DNA derived from pathogens or tumors, resulting in the production of type I interferon. Recent studies reported the role of STING in innate immune responses to RNA viruses leading to the restriction of RNA virus replication. In the current study, we found that reovirus had a reciprocal reaction with a STING agonist regarding type I interferon responses in vitro; however, we found that the combination of reovirus and STING agonist enhanced anti-tumor immunity by enhancing cytotoxic T cell trafficking into tumors, leading to significant tumor regression and survival benefit in a syngeneic colorectal cancer model. Our data indicate the combination of reovirus and a STING agonist to enhance inflammation in the tumor microenvironment might be a strategy to improve oncolytic reovirus immunotherapy.

NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-β in endometrial cancer

ObjectivesNLR family CARD domain containing 5 (NLRC5) could promote major histocompatibility complex class I (MHC-I)-dependent CD8+ T cell-mediated anticancer immunity. In this study, the immunosurveillance role and underlying mechanisms of NLRC5 in endometrial cancer (EC) were characterized. MethodsCD8+ T cells were separated from healthy women's peripheral blood by using magnetic beads. The effect of NLRC5 and interferon-β (IFN-β) on immunosurveillance of EC were examined through a mouse tumor model and a CD8+ T cell-EC cell coculture system after NLRC5 overexpression and IFN-β overexpression or depletion. The effect of NLRC5 on IFN-β expression was examined with gain- and loss-of-function experiments. ResultsNLRC5 overexpression in the EC cell and CD8+ T cell coculture system inhibited EC cell proliferation and migration and promoted EC cell apoptosis and CD8+ T cell proliferation. In vivo, NLRC5 overexpression increased the proportion of CD8+ T cells and inhibited EC progression. Furthermore, IFN-β overexpression in the EC cell and CD8+ T cell coculture system activated CD8+ T cell proliferation; however, genetic depletion of IFN-β exerted the opposite effects. In addition, NLRC5 could negatively regulate IFN-β expression in EC cells. Mechanistically, NLRC5 potentiated the antitumor responses of CD8+ T cells to EC by activating IFN-β. ConclusionsTaken together, our findings demonstrated that NLRC5 potentiates anti-tumor CD8+ T cells responses by activating interferon-β in EC, suggesting that genetically escalated NLRC5 and IFN-β may act as potential candidates for the clinical translation of adjuvant immunotherapies to patients with EC.