Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants, including BA.4 and BA.5.

After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.

Top 10 Challenges in Cancer Immunotherapy.

Cancer immunotherapy is a validated and critically important approach for treating patients with cancer. Given the vast research and clinical investigation efforts dedicated to advancing both endogenous and synthetic immunotherapy approaches, there is a need to focus on crucial questions and define roadblocks to the basic understanding and clinical progress. Here, we define ten key challenges facing cancer immunotherapy, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient. Addressing these challenges will require the combined efforts of basic researchers and clinicians, and the focusing of resources to accelerate understanding of the complex interactions between cancer and the immune system and the development of improved treatment options for patients with cancer.

The emerging role of the gut microbiome in cancer cell plasticity and therapeutic resistance.

Resistance to therapeutic agents is one of the major challenges in cancer therapy. Generally, the focus is given to the genetic driver, especially the genetic mutation behind the therapeutic resistance. However, non-mutational mechanisms, such as epigenetic modifications, and TME alteration, which is mainly driven by cancer cell plasticity, are also involved in therapeutic resistance. The concept of plasticity mainly relies on the conversion of non-cancer stem cells (CSCs) to CSCs or epithelial-to-mesenchymal transition via different mechanisms and various signaling pathways. Cancer plasticity plays a crucial role in therapeutic resistance as cancer cells are able to escape from therapeutics by shifting the phenotype and thereby enhancing tumor progression. New evidence suggests that gut microbiota can change cancer cell characteristics by impacting the mechanisms involved in cancer plasticity. Interestingly, gut microbiota can also influence the therapeutic efficacy of anticancer drugs by modulating the mechanisms involved in cancer cell plasticity. The gut microbiota has been shown to reduce the toxicity of certain clinical drugs. Here, we have documented the critical role of the gut microbiota on the therapeutic efficacy of existing anticancer drugs by altering the cancer plasticity. Hence, the extended knowledge of the emerging role of gut microbiota in cancer cell plasticity can help to develop gut microbiota-based novel therapeutics to overcome the resistance or reduce the toxicity of existing drugs. Furthermore, to improve the effectiveness of therapy, it is necessary to conduct more clinical and preclinical research to fully comprehend the mechanisms of gut microbiota.

Immunological approaches to HIV cure.

Combination antiretroviral therapy (ART) to treat human immunodeficiency virus (HIV) infection has proven remarkably successful - for those who can access and afford it - yet HIV infection persists indefinitely in a reservoir of cells, despite effective ART and despite host antiviral immune responses. An HIV cure is therefore the next aspirational goal and challenge, though approaches differ in their objectives - with 'functional cures' aiming for durable viral control in the absence of ART, and 'sterilizing cures' aiming for the more difficult to realize objective of complete viral eradication. Mechanisms of HIV persistence, including viral latency, anatomical sequestration, suboptimal immune functioning, reservoir replenishment, target cell-intrinsic immune resistance, and, potentially, target cell distraction of immune effectors, likely need to be overcome in order to achieve a cure. A small fraction of people living with HIV (PLWH) naturally control infection via immune-mediated mechanisms, however, providing both sound rationale and optimism that an immunological approach to cure is possible. Herein we review up to date knowledge and emerging evidence on: the mechanisms contributing to HIV persistence, as well as potential strategies to overcome these barriers; promising immunological approaches to achieve viral control and elimination of reservoir-harboring cells, including harnessing adaptive immune responses to HIV and engineered therapies, as well as enhancers of their functions and of complementary innate immune functioning; and combination strategies that are most likely to succeed. Ultimately, a cure must be safe, effective, durable, and, eventually, scalable in order to be widely acceptable and available.

Rewiring chaperone-mediated autophagy in cancer by a prion-like chemical inducer of proximity to counteract adaptive immune resistance.

Chaperone-mediated autophagy (CMA), a proteolytic system contributing to the degradation of intracellular proteins in lysosomes, is upregulated in tumors for pro-tumorigenic and pro-survival purposes. In this study, bioinformatics analysis revealed the co-occurrence of upregulated CMA and PD-L1 accumulation in metastatic melanoma with adaptive immune resistance (AIR) to anti-PD1 treatment, suggesting the potential therapeutic effects of rewiring CMA for PD-L1 degradation. Furthermore, this co-occurrence is attributed to IFN-γ-mediated compensatory up-regulation of PD-L1 and CMA, accompanied by enhanced macropinocytosis. Drawing inspiration from the cellular uptake of prions via macropinocytosis, a prion-like chemical inducer of proximity called SAP was engineered using self-assembly of the designed chiral peptide PHA. By exploiting sensitized macropinocytosis, SAP clandestinely infiltrates tumor cells and subsequently disintegrates into PHA, which reprograms CMA by inducing PD-L1 close to HSPA8. SAP degrades PD-L1 in a CMA-dependent manner and effectively restores the anti-tumor immune response in both allografting and Hu-PDX melanoma mouse models with AIR while upholding a high safety profile. Collectively, the reported SAP not only presents an immune reactivation strategy with clinical translational potential for overcoming AIR in cutaneous melanomas but serves as a reproducible example of precision-medicine-guided drug development that fully leverages specific cellular indications in pathological states.

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer.

Breast cancer, the most frequent female malignancy, is often curable when detected at an early stage. The treatment of metastatic breast cancer is more challenging and may be unresponsive to conventional therapy. Immunotherapy is crucial for treating metastatic breast cancer, but its resistance is a major limitation. The tumor microenvironment (TME) is vital in modulating the immunotherapy response. Various tumor microenvironmental components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), are involved in TME modulation to cause immunotherapy resistance. This review highlights the role of stromal cells in modulating the breast tumor microenvironment, including the involvement of CAF-TAM interaction, alteration of tumor metabolism leading to immunotherapy failure, and other latest strategies, including high throughput genomic screening, single-cell and spatial omics techniques for identifying tumor immune genes regulating immunotherapy response. This review emphasizes the therapeutic approach to overcome breast cancer immune resistance through CAF reprogramming, modulation of TAM polarization, tumor metabolism, and genomic alterations.

Hypoxia Reduction Sensitizes Refractory Cancers to Immunotherapy.

In order to fuel their relentless expansion, cancers must expand their vasculature to augment delivery of oxygen and essential nutrients. The disordered web of irregular vessels that results, however, leaves gaps in oxygen delivery that foster tumor hypoxia. At the same time, tumor cells increase their oxidative metabolism to cope with the energetic demands of proliferation, which further worsens hypoxia due to heightened oxygen consumption. In these hypoxic, nutrient-deprived environments, tumors and suppressive stroma evolve to flourish while antitumor immunity collapses due to a combination of energetic deprivation, toxic metabolites, acidification, and other suppressive signals. Reversal of cancer hypoxia thus has the potential to increase the survival and effector function of tumor-infiltrating T cells, as well as to resensitize tumors to immunotherapy. Early clinical trials combining hypoxia reduction with immune checkpoint blockade have shown promising results in treating patients with advanced, metastatic, and therapeutically refractory cancers.

Multiple mutations of SARS-CoV-2 Omicron BA.2 variant orchestrate its virological characteristics.

IMPORTANCE: Most studies investigating the characteristics of emerging SARS-CoV-2 variants have been focusing on mutations in the spike proteins that affect viral infectivity, fusogenicity, and pathogenicity. However, few studies have addressed how naturally occurring mutations in the non-spike regions of the SARS-CoV-2 genome impact virological properties. In this study, we proved that multiple SARS-CoV-2 Omicron BA.2 mutations, one in the spike protein and another downstream of the spike gene, orchestrally characterize this variant, shedding light on the importance of Omicron BA.2 mutations out of the spike protein.

Genetic dysregulation of immunologic and oncogenic signaling pathways associated with tumor-intrinsic immune resistance: a molecular basis for combination targeted therapy-immunotherapy for cancer.

Since the turn of the century, advances in targeted therapy and immunotherapy have revolutionized the treatment of cancer. Although these approaches have far outperformed traditional therapies in various clinical settings, both remain plagued by mechanisms of innate and acquired resistance that limit therapeutic efficacy in many patients. With a focus on tumor-intrinsic resistance to immunotherapy, this review highlights our current understanding of the immunologic and oncogenic pathways whose genetic dysregulation in cancer cells enables immune escape. Emphasis is placed on genomic, epigenomic, transcriptomic, and proteomic aberrations that influence the activity of these pathways in the context of immune resistance. Specifically, the role of pathways that govern interferon signaling, antigen processing and presentation, and immunologic cell death as determinants of tumor immune susceptibility are discussed. Likewise, mechanisms of tumor immune resistance mediated by dysregulated RAS-MAPK, WNT, PI3K-AKT-mTOR, and cell cycle pathways are described. Finally, this review highlights the ways in which recent insight into genetic dysregulation of these immunologic and oncogenic signaling pathways is informing the design of combination targeted therapy-immunotherapy regimens that aim to restore immune susceptibility of cancer cells by overcoming resistance mechanisms that often limit the success of monotherapies.

Effects of Habitual Dietary Change on the Gut Microbiota and Health of Silkworms.

Diet plays a crucial role in shaping the gut microbiota and overall health of animals. Traditionally, silkworms are fed fresh mulberry leaves, and artificial diets do not support good health. The aim of this study was to explore the relationship between the dietary transition from artificial diets to mulberry leaves and the effects on the gut microbiota and physiological changes in silkworms as a model organism. With the transition from artificial diets to mulberry leaves, the diversity of the silkworm gut microbiota increased, and the proportion of Enterococcus and Weissella, the dominant gut bacterial species in silkworms reared on artificial diets, decreased, whereas the abundance of Achromobacter and Rhodococcus increased. Dietary transition at different times, including the third or fifth instar larval stages, resulted in significant differences in the growth and development, immune resistance, and silk production capacity of silkworms. These changes might have been associated with the rapid adaptation of the intestinal microbiota of silkworms to dietary transition. This study preliminarily established a dietary transition-gut microbial model in silkworms based on the conversion from artificial diets to mulberry leaves, thus providing an important reference for future studies on the mechanisms through which habitual dietary changes affect host physiology through the gut microbiome.

Tumor immunology meets oncology (TIMO) XVI, July 07-09 2022 in Halle/Saale, Germany.

During the TIMO meeting 2022, national and international scientists as well as clinicians gave novel insights as well as perspectives into basic and translational tumor immunology.

Tumor immunology meets oncology (TIMO) XVII, April 20-22 2023 in Halle/Saale, Germany.

During the TIMO meeting 2023, national and international scientists as well as clinicians gave novel insights as well as perspectives into basic and translational tumor immunology. https://dgfi.org/arbeitskreise/ak-tumorimmunologie/meeting/.

Characterization of the Immune Resistance of Severe Acute Respiratory Syndrome Coronavirus 2 Mu Variant and the Robust Immunity Induced by Mu Infection.

BACKGROUND: We have recently revealed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mu variant shows a pronounced resistance to antibodies elicited by natural SARS-CoV-2 infection and vaccination. METHODS: However, it remains unclear which mutations determine the resistance of SARS-CoV-2 Mu to antiviral sera. In addition, it is unclear how SARS-CoV-2 Mu infection induces antiviral immunity. RESULTS: In this study, we reveal that the 2 mutations in the SARS-CoV-2 Mu spike protein, YY144-145TSN and E484K, are responsible for the resistance to coronavirus disease 2019 convalescent sera during early 2020 and vaccine sera. CONCLUSIONS: It is notable that the convalescent sera of SARS-CoV-2 Mu-infected individuals are broadly antiviral against Mu as well as other SARS-CoV-2 variants of concern and interest.

Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy.

BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.

Transcriptomic signatures of tumors undergoing T cell attack.

BACKGROUND: Studying tumor cell-T cell interactions in the tumor microenvironment (TME) can elucidate tumor immune escape mechanisms and help predict responses to cancer immunotherapy. METHODS: We selected 14 pairs of highly tumor-reactive tumor-infiltrating lymphocytes (TILs) and autologous short-term cultured cell lines, covering four distinct tumor types, and co-cultured TILs and tumors at sub-lethal ratios in vitro to mimic the interactions occurring in the TME. We extracted gene signatures associated with a tumor-directed T cell attack based on transcriptomic data of tumor cells. RESULTS: An autologous T cell attack induced pronounced transcriptomic changes in the attacked tumor cells, partially independent of IFN-γ signaling. Transcriptomic changes were mostly independent of the tumor histological type and allowed identifying common gene expression changes, including a shared gene set of 55 transcripts influenced by T cell recognition (Tumors undergoing T cell attack, or TuTack, focused gene set). TuTack scores, calculated from tumor biopsies, predicted the clinical outcome after anti-PD-1/anti-PD-L1 therapy in multiple tumor histologies. Notably, the TuTack scores did not correlate to the tumor mutational burden, indicating that these two biomarkers measure distinct biological phenomena. CONCLUSIONS: The TuTack scores measure the effects on tumor cells of an anti-tumor immune response and represent a comprehensive method to identify immunologically responsive tumors. Our findings suggest that TuTack may allow patient selection in immunotherapy clinical trials and warrant its application in multimodal biomarker strategies.

MLLT6 maintains PD-L1 expression and mediates tumor immune resistance.

Tumor cells subvert immune surveillance by harnessing signals from immune checkpoints to acquire immune resistance. The protein PD-L1 is an important component in this process, and inhibition of PD-L1 elicits durable anti-tumor responses in a broad spectrum of cancers. However, immune checkpoint inhibition that target known pathways is not universally effective. A better understanding of the genetic repertoire underlying these processes is necessary to expand our knowledge in tumor immunity and to facilitate identification of alternative targets. Here, we present a CRISPR/Cas9 screen in human cancer cells to identify genes that confer tumors with the ability to evade the cytotoxic effects of the immune system. We show that the transcriptional regulator MLLT6 (AF17) is required for efficient PD-L1 protein expression and cell surface presentation in cancer cells. MLLT6 depletion alleviates suppression of CD8+ cytotoxic T cell-mediated cytolysis. Furthermore, cancer cells lacking MLLT6 exhibit impaired STAT1 signaling and are insensitive to interferon-γ-induced stimulation of IDO1, GBP5, CD74, and MHC class II genes. Collectively, our findings establish MLLT6 as a regulator of oncogenic and interferon-γ-associated immune resistance.

Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance.

Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1-4 merkel cell carcinoma5, urological cancers6-8, non-small cell lung cancer9-11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25 to 60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15 %15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.

Sheddable Prodrug Vesicles Combating Adaptive Immune Resistance for Improved Photodynamic Immunotherapy of Cancer.

Photodynamic therapy (PDT) capable of eliciting a robust antitumor immune response has been considered an attractive therapeutic approach. However, adaptive immune resistance in PDT underlines the need to develop alternative strategies. The exquisite power of checkpoint blockade can be harnessed to reinvigorate antitumor immune response. Here, we demonstrate that PDT-triggered adaptive immune resistance can be overcome by inactivating indoleamine 2,3-dioxygenase 1 (IDO-1). We rationally designed a tumor-microenvironment-sheddable prodrug vesicle by integrating a PEGylated photosensitizer (PS) and a reduction-sensitive prodrug of IDO-1 inhibitor. The prodrug vesicles were inert during the blood circulation, whereas they specifically accumulated and penetrated at the tumor site through matrix metalloproteinase-2 (MMP-2)-mediated cleavage of the PEG corona to achieve fluorescence-imaging-guided photodynamic therapy (PDT). Compared to PDT alone, the prodrug-vesicle-mediated combination immunotherapy provoked augmented antitumor immunity to eradicate the tumor in both CT26 colorectal and 4T1 breast immunocompetent mouse models. The prodrug vesicles dramatically suppressed tumor reoccurrence, particularly in overexpressing IDO-1 tumor models, i.e., CT26. This study might provide novel insight into the development of new nanomedicine to enhance the efficacy of photodynamic immunotherapy while addressing the adaptive immune resistance.

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers.

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11-1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43-3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36-2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10-2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

Interaction between SCP3 and JAB1 Confers Cancer Therapeutic Resistance and Stem-like Properties through EGF Expression.

Synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, has been implicated in cancer progression, and therapeutic resistance, as well as cancer stem cell (CSC)-like properties. Previously, we demonstrated that SCP3 promotes these aggressive phenotypes via hyperactivation of the AKT signaling pathway; however, the underlying mechanisms responsible for SCP3-induced AKT activation remain to be elucidated. In this study, we demonstrated that the EGF-EGFR axis is the primary route through which SCP3 acts to activate AKT signaling. SCP3 triggers the EGFR-AKT pathway through transcriptional activation of EGF. Notably, neutralization of secreted EGF by its specific monoclonal antibody reversed SCP3-mediated aggressive phenotypes with a concomitant reversal of EGFR-AKT activation. In an effort to elucidate the molecular mechanisms underlying SCP3-induced transcriptional activation of EGF, we identified Jun activation domain-binding protein 1 (JAB1) as a binding partner of SCP3 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that SCP3 induces EGF transcription through physical interaction with JAB1. Thus, our findings establish a firm molecular link among SCP3, EGFR, and AKT by identifying the novel roles of SCP3 in transcriptional regulation. We believe that these findings hold important implications for controlling SCP3high therapeutic-refractory cancer.