Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development

Abstract

Abstract. Lung cancer is the most common malignancy in humans. An increased population of CD4 + Foxp3 + regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion. IntroductionLung cancer is one of the most common malignancies with severe mortality worldwide (1,2). There are ermerging treatments for lung cancer including surgery, irradiation, chemotherapy and immunotherapy. However, prognosis remains unsatisfactory (3-5). Recently, comorbid cancer-infection which represents an independent concomitant microorganism infection in tumor has attracted new attention, since certain microorganism infection might induce antitumor immunity responses for a new treatment strategy. Malaria infection significantly suppresses murine Lewis lung cancer growth via induction of innate and adaptive antitumor responses in a mouse model, suggesting that the malaria parasite may stand for a new strategy or therapeutic vaccine vector for anti-lung cancer immunotherapy (6). T. gondii infection inhibits tumor growth in the Lewis lung carcinoma mouse model through the induction of Th1 immune responses and anti-angiogenic activity (7).Mycobacterium tuberculosis (MTB) is an obligate pathogenic bacterial species in the family Mycobacteriaceae and the causative agent of tuberculosis (8). Mononuclear cells recruited to sites of MTB infection or novel MTB antigens, are exposed to MTB Toll-like receptor (TLR) ligands. MTB is rich in TLR2 ligands (9,10), and a role for TLR2 ligand in expansion of Treg has been previously shown (11). MTB and its components expand functional CD4 + Foxp3 + Treg, which implicates for effective immunization against MTB (12,13). It was also reported that active tuberculosis in non-small cell lung cancer (NSCLC) patients shows better survival outcome, possibly due to the T lymphocyte infiltration in tumors (14). However, the role of an independent H37Rv infection in the development of NSCLC is not quite clear.Here, we demonstrated that independent MTB H37Rv infection facilitated ...

Bacillus Calmette–Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer

“… 16 Zhou et al demonstrated that mycobacterium tuberculosis infection could induce increased expression of PD-L1 in macrophage by Akt-mTORC1 pathway. 17 Recently, Inman et al found that 11 of 12 patients with BCa who failed BCG immunotherapy exhibited extremely intense PD-L1 expression within the BCG granulomas of tumor tissue. 18 Heo et al also showed that normal epithelial tissues regenerated after surgical resection and BCG immunotherapy, had low expression of PD-L1, while recurred tumor showed high expression of PD-L1 after surgical resection and BCG immunotherapy.…”

Análisis de letalidad en pacientes con diagnóstico de tuberculosis en un centro de alta complejidad en Cali, Colombia

“…Nuestros hallazgos con respecto a las co-morbilidades son coherentes con lo reportado en la literatura científica, donde la principal causa de muerte en pacientes con TBC es la co-infección con SIDA y las complicaciones derivadas como otras infecciones oportunistas 1,21,22 . Se encontró en este estudio concomitancia entre TBC y cáncer en 16% de los pacientes; este hallazgo cada vez es más frecuente en la literatura médica, especialmente en cáncer de pulmón, lo que demuestra la necesidad de tamizar la infección latente por TBC de los pacientes con cáncer y evaluar la presencia de malignidad en pacientes con diagnóstico de TBC en zonas endémicas 19,23 .…”

“…La edad es variable en diferentes estudios realizados en instituciones de alta complejidad 16,17 . Con respecto al tipo de TBC extrapulmonar, la meningoencefalitis tuberculosa fue la más frecuente, la que se ha asociado a mayor mortalidad 18,19 .…”

Strain-specific behavior of Mycobacterium tuberculosis in A549 lung cancer cell line

“…Besides, the upregulation of PD-L1 expression and induction of lung carcinoma by IFN-γ have been revealed [ 30 ]. Similarly, in vitro and in vivo concomitant H37Rv infection in non-small cell lung cancer showed that lung cancer progression facilitated by enhancing Treg cells proportion and the upregulation of PD-L1 expression that induced by H37Rv as a part of M.tb lineage 4 [ 31 ]. In the current study, based on the expression of IFN-γ in response to the infection with M.tb L4.5 sub-lineage, compared to L3-CAS1 sub-lineage, this expression profile might be favor for better control of M.tb L4.5 sub-lineage strain compared to L3-CAS1 sub-lineage in infected host cell, in addition may contribute to the pathogenesis and deterioration of lung cancer during infection with M.tb L4.5 sub-lineage strain.…”