scholarly journals Subversion of host defense mechanisms by murine tumors. II. Counter-influence of concomitant antitumor immunity.

1976 ◽  
Vol 143 (3) ◽  
pp. 574-584 ◽  
Author(s):  
R J North ◽  
D P Kirstein ◽  
R L Tuttle
Keyword(s):  
Tumor Cell ◽  
Host Defense ◽  
Primary Tumor ◽  
Defense Mechanisms ◽  
Antitumor Immunity ◽  
Malignant Tumors ◽  
Acquired Resistance ◽  
Antibacterial Resistance ◽  
Stages Of Growth ◽  
Murine Tumor Cells

Subcutaneous injection of murine tumor cells first resulted in a state of severely suppressed macrophage-mediated antibacterial resistance and then in a contrasting state of greatly enhanced antibacterial resistance. Whereas, the state of suppressed antibacterial resistance corresponded to a state of suppressed resistance to a tumor cell challenge, the generation of enhanced antibacterial resistance corresponded to the acquisition of concomitant antitumor immunity. It was suggested on the basis of this evidence that changes in the level of macrophage-mediated antibacterial resistance that occur during growth of the primary tumor reflected changes in the level of the host's resistance to the tumor itself. It was further suggested that the coincidental suppression of antibacterial and antitumor resistance that occurs during the initial stages of growth of the primary tumor represents the operation of a mechanism that enables the tumor to avoid destruction by macrophages. The results support the view that macrophages play an important role in native and acquired resistance to malignant tumors.

scholarly journals Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

2020 ◽  
Vol 8 (2) ◽  
pp. e001182 ◽  
Author(s):  
Henrique Lemos ◽  
Rong Ou ◽  
Caroline McCardle ◽  
Yijun Lin ◽  
Jessica Calver ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Primary Tumor ◽  
Antitumor Immunity ◽  
Acquired Resistance ◽  
Tumor Control ◽  
Regulatory Pathways ◽  
Beneficial Effects ◽  
Immune Balance ◽  
Promote Tumor Growth ◽  
Inhibitor Drug

BackgroundActivating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts antitumor responses in mice bearing LLC tumors.MethodsMice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective antitumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways.ResultsCDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental end points but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving programmed death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO) and cyclooxygenase-2 (COX2) in the TME. PD-1 blockade enhanced antitumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on antitumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and celecoxib acquired stable and systemic antitumor immunity.ConclusionsSTING activation incites potent antitumor responses and boosts local immune regulation to attenuate antitumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance antitumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in patients with cancer.

scholarly journals Subversion of host defense mechanisms by malignant tumors: an established tumor as a privileged site for bacterial growth.

1977 ◽  
Vol 145 (5) ◽  
pp. 1264-1277 ◽  
Author(s):  
G L Spitalny ◽  
R J North
Keyword(s):  
T Cells ◽  
Host Defense ◽  
Defense Mechanisms ◽  
Malignant Tumors ◽  
Activated Macrophages ◽  
Established Tumor ◽  
Hind Foot ◽  
Foot Pad ◽  
Privileged Site ◽  
Contralateral Tumor

Mice carrying any one of three murine tumors in their right hind foot pad were incapable of eliminating an inoculum of the bacterial parasite Listeria monocytogenes from the progressive tumor. In contrast, they were as capable as control mice in efficiently eliminating the organism from their contralateral tumor-free foot pad, and from their lymph nodes and livers. The results serve to show, therefore, that conditions within an established tumor are not only antagonistic to the expression of concomitant anti-tumor immunity, but that they are also antagonistic to the expression of T-cell-mediated anti-bacterial immunity. The possibility was discussed that the tumor contains factors that act pharmacologically to locally suppress the function of sensitized T cells and activated macrophages.

scholarly journals Application Research of Individualized Conditional Reprogramming System to Guide Treatment of Gastric Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Weizhu Zhao ◽  
Kai Liu ◽  
Zhikun Sun ◽  
Longgang Wang ◽  
Bing Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Cell ◽  
Primary Tumor ◽  
Drug Sensitivity ◽  
Malignant Tumors ◽  
Chemotherapeutic Agents ◽  
Cell Bank ◽  
Chemotherapy Drugs ◽  
Primary Tumor Cell ◽  
Cr System

BackgroundGastric cancer (GC) is one of the most common causes of malignant tumors in the world. Due to the high heterogeneity of GC and lack of specificity of available chemotherapy regimens, these tumors are prone to resistance, recurrence, and metastasis. Here, we formulated an individualized chemotherapy regimen for GC using a modified individual conditional reprogramming (i-CR) system. We established a primary tumor cell bank of GC cells and completed drug screening in order to realize individualized and accurate GC treatment.MethodsWe collected specimens from 93 surgical or gastroscopy GC cases and established a primary tumor cell bank using the i-CR system and PDX models. We also completed in vitro culture and drug sensitivity screening of the GC cells using the i-CR system. Whole-exome sequencing (WES) of the i-CR cells was performed using P0 and P5. We then chose targeted chemotherapy drugs based on the i-CR system results.ResultsOf the 72 cases that were collected from surgical specimens, 26 cases were successfully cultured with i-CR system, and of the 21 cases collected from gastroscopy specimens, seven were successfully cultured. Among these, 20 cases of the PDX model were established. SRC ± G3 had the highest culture success rate. The i-CR cells of P0 and P5 appeared to be highly conserved. According to drug sensitivity screening, we examined the predictive value of responses of GC patients to chemotherapeutic agents, especially in neoadjuvant patients.ConclusionThe i-CR system does not only represent the growth characteristics of tumors in vivo, but also provides support for clinical drug use. Drug susceptibility results were relatively consistent with clinical efficacy.

Effects of Anesthesia, Surgery and Inflammation Upon Host Defense Mechanisms

1975 ◽  
Vol 48 (5) ◽  
pp. 706-720 ◽  
Author(s):  
M. Schutte ◽  
R. DiCamelli ◽  
P. Murphy ◽  
M. Sadove ◽  
H. Gewurz
Keyword(s):  
Host Defense ◽  
Defense Mechanisms

scholarly journals The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung

2021 ◽  
Vol 22 (5) ◽  
pp. 2566 ◽  
Author(s):  
Barbara Ruaro ◽  
Francesco Salton ◽  
Luca Braga ◽  
Barbara Wade ◽  
Paola Confalonieri ◽  
...  
Keyword(s):  
Host Defense ◽  
Defense Mechanisms ◽  
Work Of Breathing ◽  
Surfactant Proteins ◽  
Alveolar Type ◽  
Type I ◽  
Type Ii ◽  
Lung Protection ◽  
Alveolar Epithelial ◽  
Distal Lung

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air–liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.

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