Bacterial Infection and Non-Hodgkin B-Cell Lymphoma: Interactions between Pathogen, Host and the Tumor Environment

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B-cell non-Hodgkin lymphomas (B-NHLs). In the last decade, the emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma such as diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

Section: B-cell Receptor (Bcr) Signalingmentioning

confidence: 99%

Regulation of B-Cell Receptor Signaling and Its Therapeutic Relevance in Aggressive B-Cell Lymphomas

Profitós-Pelejà

Santos

Marín‐Niebla

et al. 2022

“…In addition to gastric MALT lymphoma, which is significantly associated with HP infection, increasing evidence demonstrates that C. jejuni , C. psittaci , and Borrelia burgdorferi are associated with IPSID, OAML, and cutaneous MALT lymphoma, respectively [ 56 , 57 , 58 , 59 , 60 ]. IPSID, an endemic disease, mainly occurs in the Mediterranean and sporadically in Western and Asian countries [ 10 , 20 , 56 , 61 ].…”

Section: Efficacies Of First-line Antibiotics Treatment For Extragast...mentioning

confidence: 99%

“…Patients with cutaneous MALT lymphoma often present with asymptomatic single papules, plaques, or nodules before diagnosis, and certain patients demonstrate serum antibody positivity for B. burgdorferi [ 60 ]. In endemic areas of Europe, the prevalence of B. burgdorferi was approximately 10% to 42% in patients with cutaneous MALT lymphoma through PCR analyses of B. burgdorferi DNA [ 59 ].…”

Section: Efficacies Of First-line Antibiotics Treatment For Extragast...mentioning

confidence: 99%

“…In endemic areas of Europe, the prevalence of B. burgdorferi was approximately 10% to 42% in patients with cutaneous MALT lymphoma through PCR analyses of B. burgdorferi DNA [ 59 ]. Based on the indolent course of most patients with cutaneous MALT lymphoma, the administration of first-line antibiotics using cephalosporins and tetracyclines is reasonable based on case reports demonstrating the antibiotic responsiveness of B. burgdorferi -positive cutaneous MALT lymphoma [ 59 , 60 , 65 ]. In a meta-analysis of 506 patients with primary cutaneous lymphoma obtained from 10 studies, Travaglino et al showed that the prevalence of B. burgdorferi infection confirmed by PCR assay of B. burgdorferi DNA was significantly associated with B-cell lymphoma, including MALT lymphoma, and the positivity rate for B. burgdorferi in primary cutaneous MALT lymphoma was 8.3% [ 66 ].…”

Section: Efficacies Of First-line Antibiotics Treatment For Extragast...mentioning

confidence: 99%

See 1 more Smart Citation

Current Status of the Spectrum and Therapeutics of Helicobacter pylori-Negative Mucosa-Associated Lymphoid Tissue Lymphoma

Kuo

Yeh

Lin

et al. 2022

Helicobacter pylori (HP)-unrelated mucosa-associated lymphoid tissue (MALT) lymphoma includes the majority of extragastric MALT lymphomas and a small proportion of gastric MALT lymphomas. Although the role of first-line antibiotics in treating HP-negative gastric MALT lymphomas remains controversial, HP eradication therapy (HPE)-like regimens may result in approximately 20–30% complete remission (CR) for patients with localized HP-negative gastric MALT lymphoma. In these patients, H. heilmannii, H. bizzozeronii, and H. suis were detected in sporadic gastric biopsy specimens. Extragastric MALT lymphoma is conventionally treated with radiotherapy for localized disease and systemic chemotherapy for advanced and metastatic diseases. However, a proportion of extragastric MALT lymphomas, such as ocular adnexal lesions and small intestinal lesions, were reported to be controlled by antibiotics for Chlamydophila psittaci and Campylobacter jejuni, respectively. Some extragastric MALT lymphomas may even respond to first-line HPE. These findings suggest that some antibiotic-responsive tumors may exist in the family of HP-negative MALT lymphomas. Two mechanisms underlying the antibiotic responsiveness of HP-negative MALT lymphoma have been proposed. First, an HPE-like regimen may eradicate the antigens of unknown bacteria. Second, clarithromycin (the main component of HPE) may have direct or indirect antineoplastic effects, thus contributing to the CR of these tumors. For antibiotic-unresponsive HP-negative MALT lymphoma, high-dose macrolides and immunomodulatory drugs, such as thalidomide and lenalidomide, have reported sporadic success. Further investigation of new treatment regimens is warranted.

“…Inadequate oral hygiene can facilitate the growth of photogenic bacteria in the oral cavity. Dysbiosis leads to local and systemic inflammation, which is known to promote oncogenesis; an example of this is Helicobacter Pylori infection in the stomach and the development of mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) [ 26 ]. One of the most commonly known mechanisms is overexpression of Toll-like receptor 5 (TLR5).…”

Section: Hnc—risk Factors and Carcinogenesismentioning

confidence: 99%

Is There an Interplay between Oral Microbiome, Head and Neck Carcinoma and Radiation-Induced Oral Mucositis?

Gugnacki

Sierko

2021

Head and neck carcinoma is one of the most common human malignancy types and it ranks as the sixth most common cancer worldwide. Nowadays, a great potential of microbiome research is observed in oncology—investigating the effect of oral microbiome in oncogenesis, occurrence of treatment side effects and response to anticancer therapies. The microbiome is a unique collection of microorganisms and their genetic material, interactions and products residing within the mucous membranes. The aim of this paper is to summarize current research on the oral microbiome and its impact on the development of head and neck cancer and radiation-induced oral mucositis. Human microbiome might determine an oncogenic effect by, among other things, inducing chronic inflammatory response, instigating cellular antiapoptotic signals, modulation of anticancer immunity or influencing xenobiotic metabolism. Influence of oral microbiome on radiation-induced oral mucositis is expressed by the production of additional inflammatory cytokines and facilitates progression and aggravation of mucositis. Exacerbated acute radiation reaction and bacterial superinfections lead to the deterioration of the patient’s condition and worsening of the quality of life. Simultaneously, positive effects of probiotics on the course of radiation-induced oral mucositis have been observed. Understanding the impact on the emerging acute radiation reaction on the composition of the microflora can be helpful in developing a multifactorial model to forecast the course of radiation-induced oral mucositis. Investigating these processes will allow us to create optimized and personalized preventive measures and treatment aimed at their formation mechanism. Further studies are needed to better establish the structure of the oral microbiome as well as the dynamics of its changes before and after therapy. It will help to expand the understanding of the biological function of commensal and pathogenic oral microbiota in HNC carcinogenesis and the development of radiation-induced oral mucositis.