Immunogenicity Threshold in Allogeneic Cells Impacts CTL Response to Nondominant Congenic Antigens.

Transplantation and cancer expose the immune system to neoantigens, including immunogenic (dominant and subdominant) and nonimmunogenic Ags with varying quantities and affinities of immunodominant peptides. Conceptually, immunity is believed to mainly target dominant Ags when subdominant or nondominant Ags are linked within the same cell due to T cell interference. This phenomenon is called immunodominance. However, our previous study in mice showed that linked nonimmunogenic Ags (OVA and GFP) containing immunodominant peptides mount immunity irrespective of the MHC-matched allogeneic cell's immunogenicity. Consequently, we further explored 1) under what circumstances does the congenic marker CD45.1 provoke immunity in CD45.2 mice, and 2) whether linking two dominant or subdominant Ags can instigate an immune response. Our observations showed that CD45.1 (or CD45.2), when connected to low-immunogenic cell types is presented as an immunogen, which contrasts with its outcome when linked to high-immunogenic cell types. Moreover, we found that both dominant and subdominant Ags are presented as immunogens when linked in environments with lower immunogenic thresholds. These findings challenge the existing perception that immunity is predominantly elicited against dominant Ags when linked to subdominant or nondominant Ags. This study takes a fundamental step toward understanding the nuanced relationship between immunogenic and nonimmunogenic Ags, potentially opening new avenues for comprehending cancer immunoediting and enhancing the conversion of cold tumors with low immunogenicity into responsive hot tumors.

Natural Antibodies Alert the Adaptive Immune System of the Presence of Transformed Cells in Early Tumorigenesis.

Recent studies have revealed a critical role for natural Abs (NAbs) in antitumor immune responses. However, the role of NAbs in cancer immunosurveillance remains unexplored, mainly because of the lack of in vivo models that mimic the early recognition and elimination of transforming cells. In this article, we propose a role for NAbs in alerting the immune system against precancerous neoantigen-expressing cells immediately after they escape intrinsic tumor suppression mechanisms. We identify four distinct reproducible, trackable, MHC-matched neoantigen-expressing cell models that do not form tumors as the end point. This amplified readout in the critical window prior to tumor formation allows investigation of new mediators of cancer immunosurveillance. We found that neoantigen-expressing cells adoptively transferred in NAb-deficient mice persisted, whereas they were eliminated in wild-type mice, indicating that the circulating NAb repertoire alerts the immune system to the presence of transformed cells. Moreover, immunity is mounted against immunogenic and nonimmunogenic neoantigens contained in the NAb-tagged cells, regardless of whether the NAb directly recognizes the neoantigens. Beyond these neoantigen-expressing model systems, we observed a significantly greater tumor burden in chemically and virally induced tumor models in NAb-deficient mice compared with wild-type mice. Restoration of the NAb repertoire in NAb-deficient mice elicited the recognition and elimination of neoantigen-expressing cells and cancer. These data show that NAbs are required and sufficient for elimination of transformed cells early in tumorigenesis. These models can now be used to investigate how NAbs stimulate immunity via recognition receptors to eliminate precancerous cells.

Neutrophil-derived granule cargoes: paving the way for tumor growth and progression.

Neutrophils are the key cells of our innate immune system mediating host defense via a range of effector functions including phagocytosis, degranulation, and NETosis. For this, they employ an arsenal of anti-microbial cargoes packed in their readily mobilizable granule subsets. Notably, the release of granule content is tightly regulated; however, under certain circumstances, their unregulated release can aggravate tissue damage and could be detrimental to the host. Several constituents of neutrophil granules have also been associated with various inflammatory diseases including cancer. In cancer setting, their excessive release may modulate tissue microenvironment which ultimately leads the way for tumor initiation, growth and metastasis. Neutrophils actively infiltrate within tumor tissues, wherein they show diverse phenotypic and functional heterogeneity. While most studies are focused at understanding the phenotypic heterogeneity of neutrophils, their functional heterogeneity, much of which is likely orchestrated by their granule cargoes, is beginning to emerge. Therefore, a better understanding of neutrophil granules and their cargoes will not only shed light on their diverse role in cancer but will also reveal them as novel therapeutic targets. This review provides an overview on existing knowledge of neutrophil granules and detailed insight into the pathological relevance of their cargoes in cancer. In addition, we also discuss the therapeutic approach for targeting neutrophils or their microenvironment in disease setting that will pave the way forward for future research.

Neutrophils as emerging protagonists and targets in chronic inflammatory diseases.

INTRODUCTION: Neutrophils are the key cells of our innate immune system with a primary role in host defense. They rapidly arrive at the site of infection and display a range of effector functions including phagocytosis, degranulation, and NETosis to eliminate the invading pathogens. However, in recent years, studies focusing on neutrophil biology have revealed the highly adaptable nature and versatile functions of these cells which extend beyond host defense. Neutrophils are now referred to as powerful mediators of chronic inflammation. In several chronic inflammatory diseases, their untoward actions, such as immense infiltration, hyper-activation, dysregulation of effector functions, and extended survival, eventually contribute to disease pathogenesis. Therefore, a better understanding of neutrophils and their effector functions in prevalent chronic diseases will not only shed light on their role in disease pathogenesis but will also reveal them as novel therapeutic targets. METHODS: We performed a computer-based online search using the databases, PubMed.gov and Clinical trials.gov for published research and review articles. RESULTS AND CONCLUSIONS: This review provides an assessment of neutrophils and their crucial involvement in various chronic inflammatory disorders ranging from respiratory, neurodegenerative, autoimmune, and cardiovascular diseases. In addition, we also discuss the therapeutic approach for targeting neutrophils in disease settings that will pave the way forward for future research.

Identification of MΦ specific POTEE expression: Its role in mTORC2 activation via protein-protein interaction in TAMs.

POTE is known as cancer antigen, expressed in many cancers, along with very few normal tissues like prostate, ovary, testes and embryo. Till date, POTEE identified as majorly expressed POTE paralog. Functionally, POTEF regulates TLR signaling which play important role in innate immunity provided clue about expression of POTE in immune cells. We have chosen three Thp1monocytes, Jurkat T1 and MΦ cells as a model. Here, first time we report expression of POTEE in immune cells specifically only in MΦ but not in monocytes or T-cells. In addition, expression level remains unaltered in MΦ subtypes M1 and M2 and MΦ subjected to various stresses, except MΦs treated with Hyp-CM where MΦs acquires properties of TAMs. In TAMs, POTEE was involved differential protein-protein interaction with mTOR, RICTOR, and Rad51 indicating its biological role in cell invasion through mTORC2 activation. siRNA mediated knockdown of POTEE suggests its importance in cell survival of MΦs as well as TAMs.

Amelioration of Dalton's lymphoma-induced angiogenesis by melatonin.

For tumor to grow beyond 1-2 mm3 size, tumor recruits new blood vessels referred as angiogenesis; therefore, targeting angiogenesis can be a promising strategy to suppress cancer progression. In this study, in order to develop a good angiogenesis model, we investigated effect of Dalton's lymphoma on angiogenesis and further monitored the role of melatonin on regulation of angiogenesis. To evaluate angiogenesis, endothelial cells were isolated from main thoracic aorta and cultured in vitro in the presence or absence of Dalton's lymphoma supplemented with or without melatonin to monitor their role on its proliferation and migration, a hallmark of angiogenesis. Chick chorioallantoic membrane as well as mice mesentery which allows in vivo studies of tumor angiogenesis and testing of anti-angiogenic molecules was used to validate the in vitro analysis. To further extend our understanding about the regulation of the angiogenesis, we evaluated expression of tissue inhibitor of metalloproteinases 3, vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor in Dalton's lymphoma cells and mesentery by semiquantitative and quantitative reverse transcription polymerase chain reaction analysis. Dalton's lymphoma ascites induced significant increase in endothelial cell proliferation, migration, and sprouting of the tertiary branching in chorioallantoic membrane and mesentery of Dalton's lymphoma-bearing mice, whereas melatonin treatment led to their inhibition in a dose-dependent manner. Semiquantitative and quantitative reverse transcription polymerase chain reaction analysis of melatonin-treated Dalton's lymphoma cells and mesentery tissue clearly demonstrated restoration of angiogenesis-related genes tissue inhibitor of metalloproteinases 3 and reduction of vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor messenger RNA expression. Taken together, our results strongly demonstrate that Dalton's lymphoma provides pro-angiogenic environment leading to significant increase in angiogenesis, and further melatonin treatment reduced the Dalton's lymphoma ascites-induced angiogenesis implying that Dalton's lymphoma can serve as a very good model to study angiogenesis as well as for screening of drugs that can target angiogenesis.

Myopathy: Effect of Vitamin D Deficiency Beyond Bones.

Vitamin D functions as a vitamin as well as a hormone. Its major skeletal actions are complemented by varied extra-skeletal functions. During the past decade, association between Vitamin D and its role in various non-skeletal morbidities have been recognized. It plays a role in decreasing the risk of many chronic illnesses like allergies, asthma, autoimmune diseases, diabetes, cancers, infections and cardiovascular disease. We report the case of a middle aged female with chronic quadriparesis and new onset anemia associated with Vitamin D deficiency. Patient responded to vitamin D supplementation alone.

Dithiocarbamate-thiourea hybrids useful as vaginal microbicides also show reverse transcriptase inhibition: design, synthesis, docking and pharmacokinetic studies.

Prophylactic prevention is considered as the most promising strategy to tackle STI/HIV. Twenty-five dithiocarbamate-thiourea hybrids (14-38) were synthesized as woman controlled topical vaginal microbicides to counter Trichomonas vaginalis and sperm along with RT inhibition potential. The four promising compounds (18, 26, 28 and 33) were tested for safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. Docking study of most promising vaginal microbicide (33) revealed that it docked in a position and orientation similar to known reverse transcriptase inhibitor Nevirapine. The preliminary in vivo pharmacokinetics of compound 33 was performed in NZ-rabbits to evaluate systemic toxicity in comparison to Nonoxynol-9.

Case Series of Pancreatitis with Uncommon Presentations.

Acute pancreatitis is an inflammatory disease characterized by local tissue injury which can trigger a systemic inflammatory response. Vascular complications of pancreatitis are a major cause of morbidity and mortality. Pulmonary embolism in acute pancreatitis has been reported to be very rare. Cardiovascular complications include shock, hypovolemia, pericardial effusion, and even nonspecific ST-T changes in the electrocardiogram (ECG) mimicking acute myocardial infarction. Acute pancreatitis complicated with acute myocardial infarction has rarely been reported and the precise mechanisms of myocardial injury remain unclear. Here we report two cases of acute pancreatitis one with acute pulmonary thrombo embolism and other with acute myocardial injury.

Melatonin modulates L-arginine metabolism in tumor-associated macrophages by targeting arginase 1 in lymphoma.

L-Arginine metabolism plays a crucial role in determining the M1/M2 polarization of macrophages. The M1 macrophages express inducible nitric oxide synthase (iNOS), while the M2 macrophages express arginase 1 and metabolize arginine into nitric oxide and urea, respectively. The tumor microenvironment promotes M2 macrophage polarization and consequently switches the metabolic fate of arginine from nitric oxide towards urea production. Importantly, infiltration of M2 macrophages or tumor-associated macrophages (TAMs) has been correlated with poor prognosis of various cancer types. Melatonin is well reported to have antitumor and immunomodulatory properties. However, whether and how it impacts the polarization of TAMs has not been elucidated. Considering the crucial role of arginine metabolism in macrophage polarization, we were interested to know the fate of L-arginine in TAMs and whether it can be reinstated by melatonin or not. We used a murine model of Dalton's lymphoma and established an in vitro model of TAMs. For TAMs, we used the ascitic fluid of tumor-bearing hosts to activate the macrophages in the presence and absence of lipopolysaccharide (LPS). In these groups, L-arginine metabolism was evaluated, and then the effect of melatonin was assessed in these groups, wherein the metabolic fate of arginine as well as the expression of iNOS and arginase 1 were checked. Furthermore, in the in vivo system of the tumor-bearing host, the effect of melatonin was assessed. The in vitro model of TAMs showed a Th2 cytokine profile, reduced phagocytic activity, and increased wound healing ability. Upon investigating arginine metabolism, we observed high urea levels with increased activity and expression of arginase 1 in TAMs. Furthermore, we observed reduced levels of LPS-induced nitric oxide in TAMs; however, their iNOS expression was comparable. With melatonin treatment, urea level decreased significantly, while the reduction in nitric oxide level was not as significant as observed in its absence in TAMs. Also, melatonin significantly reduced arginase activity and expression at the transcriptional and translational levels, while iNOS expression was affected only at the translational level. This effect was further investigated in the in vivo system, wherein melatonin treatment reversed the metabolic fate of arginine, from urea towards nitric oxide, within the tumor microenvironment. This effect was further correlated with pro-apoptotic tumor cell death in the in vivo system. Our results reinforced the immunomodulatory role of melatonin and offered a strong prospect for activating the anti-tumor immune response in cancer conditions.

Natural antibodies drive type 2 immunity in response to damage-associated molecular patterns.

Allergic airway disease (AAD) is an example of type 2 inflammation that leads to chronic airway eosinophilia controlled by CD4 Th2 cells. Inflammation is reinforced by mast cells and basophils armed with allergen-specific IgE made by allergen-specific B2 B cells of the adaptive immune system. Little is known about how AAD is affected by innate B1 cells, which produce natural antibodies (NAbs) that facilitate apoptotic cell clearance and detect damage- and pathogen-associated molecular patterns (DAMPS and PAMPS). We used transgenic mice lacking either B cells or NAbs in distinct mouse models of AAD that require either DAMPS or PAMPS as the initial trigger for type 2 immunity. In a DAMP-induced allergic model, driven by alum and uric acid, mouse strains lacking B cells (CD19DTA), NAbs (IgHEL MD4), or all secreted antibodies (sIgm-/-Aid-/-) displayed a significant reduction in both eosinophilia and Th2 priming compared with WT or Aid-/- mice lacking only germinal center-dependent high-affinity class-switched antibodies. Replenishing B cell-deficient mice with either unimmunized B1 B cells or NAbs during sensitization restored eosinophilia, suggesting that NAbs are required for licensing antigen-presenting cells to prime type 2 immunity. Conversely, PAMP-dependent type 2 priming to house dust mite or Aspergillus was not dependent on NAbs. This study reveals an underappreciated role of B1 B cell-generated NAbs in selectively driving DAMP-induced type 2 immunity.

High-Dimensional Analyses Reveal IL15 Enhances Activation of Sipuleucel-T Lymphocyte Subsets and Reverses Immunoresistance.

Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ∼60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2- to 14-fold higher influx of sip-T and a significant increase in IFNγ producing CD8+ T cells and NKT cells within the tumor microenvironment in the IL15 group. In conclusion, we put forward evidence that IL15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL15 or IL15 agonists with sip-T to treat patients with mCRPC.

A novel role of Tinospora cordifolia in amelioration of cancer-induced systemic deterioration by taming neutrophil infiltration and hyperactivation.

BACKGROUND: Cancer has emerged as a systemic disease which targets various organs thus challenging the overall physiology of the host. Recently, we have shown that hyperactive neutrophils infiltrate various organs of tumor bearing host and contribute to gradual systemic deterioration. Therefore, taming neutrophils via potent immunomodulators could be an appropriate therapeutic approach in regulating systemic damage. Tinospora cordifolia (TC), an Ayurvedic panacea, is known for its immense medicinal values in traditional literature and recent reports have also documented its immunomodulatory potential. However, whether TC can regulate neutrophils to exert its therapeutic effectiveness has not been deciphered so far. METHODS: For the in vivo study, we utilized murine model of Dalton's Lymphoma (DL). T. cordifolia extract (TCE) treatment was scheduled at early, mid and advanced stages of tumor growth at a dose of 400 mg/kg b.w for 30 consecutive days. Effect of TCE on neutrophil infiltration was examined by immunostaining. Neutrophil elastase (NE) level in serum, ascitic fluid and various tissues was monitored by ELISA. Further, qPCR was performed to assess transcripts levels of NE, myeloperoxidase (MPO), metalloproteinases (MMP-8, MMP-9) and cathepsin G (CSTG) in various tissues. ROS level in tissue was assessed by DHE staining and organ function was assessed by histology post TCE treatment. RESULTS: Our findings showed that TC treatment significantly reduced neutrophil count in peripheral blood and their infiltration in vital organs of tumor-bearing host. Further, it ameliorated neutrophil hyperactivation by down regulating the expression of its key cargoes including NE, MPO, MMP-8, MMP-9 and CSTG at early and mid stage of tumor growth. In addition, TC treatment prevented histopathological alterations and restored the normal serum enzyme levels at different stages of tumor growth. Importantly, TC treatment also showed significant reduction in tumor burden which was accompanied by a remarkable increase in survival of the tumor-bearing mice. CONCLUSIONS: We conclude that T. cordifolia could limit systemic damage via regulating neutrophil infiltration and hyperactivation which can further lead to cancer control at both prophylactic and therapeutic level.

Channeling antigens to CD8+ T cells.

Perforin-2 facilitates antigen translocation to the cytosol in cross-presenting dendritic cells.

Comparative In Vitro Anticancer Study of Cisplatin Drug with Green Synthesized ZnO Nanoparticles on Cervical Squamous Carcinoma (SiHa) Cell Lines.

In this article, we aimed to develop a unique treatment approach to cure cervical cancer without harming healthy normal cells and overcome the limitations of currently available therapies/treatments. Recently, chemotherapeutics based on metal oxides have gained attention as a promising approach for treating cancer. Herein, ZnO nanoparticles were synthesized with the leaf extract of Azadirachta indica. These green synthesized ZnO nanoparticles were used for a cytotoxic study on the cervical squamous carcinoma cell line SiHa and murine macrophage cell line RAW 264.7. Moreover, a hemolytic assay was performed to check the biocompatibility of ZnO nanoparticles. The biosynthesized ZnO nanoparticles were labeled as L1, L2, L5, and L10 nanoparticles. Various assays like crystal violet, MTT assay, and AO/PI dual staining method were performed to assess the anticancer potential of ZnO. The concentration of ZnO nanoparticles was taken in the range of 100-250 µg/mL in the in vitro anticancer study on SiHa cancer cell lines. The findings of the MTT assay revealed that biosynthesized ZnO nanoparticles exhibited significant cytotoxicity against SiHa cancer cell lines dose-dependently at two incubation times (24 and 48 h). Also, a decrease in cell viability was observed with an increased concentration of ZnO. The IC50 values obtained were 141 µg/mL for L1, 132 µg/mL for L2, 127 µg/mL for L5, and 115 µg/mL for L10 nanoparticles. In addition, cisplatin drug (10 µg/mL) was also used to compare the anticancer activity with the biosynthesized L1, L2, L5, and L10 nanoparticles. The results of the crystal violet assay and AO/PI dual staining method revealed that morphological changes like cell shrinkage, poor cell adhesion, and induction of apoptosis occurred in the SiHa cancer cell lines. Furthermore, the stability of the ZnO nanoparticles at physiological pH has been assessed by recording the UV-visible spectrum at various pH values. Hence, the overall findings suggested that biosynthesized ZnO nanoparticles can be utilized for cervical squamous cancer treatment in addition to the current treatment strategies/techniques.

CCL5-producing migratory dendritic cells guide CCR5+ monocytes into the draining lymph nodes.

Dendritic cells (DCs) and monocytes capture, transport, and present antigen to cognate T cells in the draining lymph nodes (LNs) in a CCR7-dependent manner. Since only migratory DCs express this chemokine receptor, it is unclear how monocytes reach the LN. In steady-state and following inhalation of several PAMPs, scRNA-seq identified LN mononuclear phagocytes as monocytes, resident, or migratory type 1 and type 2 conventional (c)DCs, despite the downregulation of Xcr1, Clec9a, H2-Ab1, Sirpa, and Clec10a transcripts on migratory cDCs. Migratory cDCs, however, upregulated Ccr7, Ccl17, Ccl22, and Ccl5. Migratory monocytes expressed Ccr5, a high-affinity receptor for Ccl5. Using two tracking methods, we observed that both CD88hiCD26lomonocytes and CD88-CD26hi cDCs captured inhaled antigens in the lung and migrated to LNs. Antigen exposure in mixed-chimeric Ccl5-, Ccr2-, Ccr5-, Ccr7-, and Batf3-deficient mice demonstrated that while antigen-bearing DCs use CCR7 to reach the LN, monocytes use CCR5 to follow CCL5-secreting migratory cDCs into the LN, where they regulate DC-mediated immunity.

A paracrine circuit of IL-1ß/IL-1R1 between myeloid and tumor cells drives genotype-dependent glioblastoma progression.

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1ß in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1ß/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1ß/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1ß, IL-1α exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively active NF-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1ß could be considered as an effective therapy specifically for proneural GBM.

Pharmacological Inhibition of Exosome Machinery: An Emerging Prospect in Cancer Therapeutics.

Exosomes are nanocarriers that mediate intercellular communication crucial for normal physiological functions. However, exponentially emerging reports have correlated their dysregulated release with various pathologies, including cancer. In cancer, from stromal remodeling to metastasis, where tumor cells bypass the immune surveillance and show drug resistivity, it has been established to be mediated via tumor-derived exosomes. Owing to their role in cancer pathogenicity, exosomebased strategies offer enormous potential in treatment regimens. These strategies include the use of exosomes as a drug carrier or as an immunotherapeutic agent, which requires advanced nanotechnologies for exosome isolation and characterization. In contrast, pharmacological inhibition of exosome machinery surpasses the requisites of nanotechnology and thus emerges as an essential prospect in cancer therapeutics. In this line, researchers are currently trying to dissect the molecular pathways to reveal the involvement of key regulatory proteins that facilitate the release of tumor-derived exosomes. Subsequently, screening of various molecules in targeting these proteins, with eventual abatement of exosome-induced cancer pathogenicity, is being done. However, their clinical translation requires more extensive studies. Here, we comprehensively review the molecular mechanisms regulating exosome release in cancer. Moreover, we provide insight into the key findings that highlight the effect of various drugs as exosome blockers, which will add to the route of drug development in cancer management.

Hyperactive neutrophils infiltrate vital organs of tumor bearing host and contribute to gradual systemic deterioration via upregulated NE, MPO and MMP-9 activity.

Cancer is known to have systemic impact by targeting various organs that ultimately compromises the overall physiology of the host. Several reports have demonstrated the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, their role in mediating systemic effects during cancer progression has not been deciphered so far. Therefore, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern their systemic role, we evaluated neutrophil count and function at different stages of tumor growth in Dalton's Lymphoma mice model. Notably, our results displayed a gradual increase in Ly6G+ neutrophils in peripheral blood and their infiltration in vital organs including liver, lungs, spleen, kidney, lymph nodes and peritoneum of tumor bearing host. We showed remarkable alterations in histoarchitecture and serum enzyme levels that aggravated with tumor progression. We next examined neutrophil function by assessing its granular cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), and matrix metalloproteinases (MMP-8 and MMP-9). Interestingly, blood neutrophils of tumor bearing mice exhibited a marked change in morphology with gradual increase in NE and MPO expression with tumor growth. In addition, we observed upregulated expression of NE, MPO, MMP-8 and MMP-9 in the vital organs of tumor bearing host. Taken together, our results demonstrate heightened infiltration and function of neutrophils in vital organs of tumor bearing host which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.