We engrafted mice with primary B16-OVA or B16-F10 tumors on a single flank. metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control. Introduction tumor ablative strategies, including radiofrequency ablation and cryoablation, are effective at destroying localized disease and may stimulate the host immune system to recognize and eliminate remaining tumor cells [1]C[4]. Tumor ablation induces necrotic and apoptotic tumor cell Y16 death by direct cytotoxicity and destruction of the tumor microvasculature [5]. Because dying tumor cells provide a source of tumor antigens and induce the expression of natural immune adjuvants, like heat shock proteins [6]C[9] and alarmins [10], they initiate an inflammatory cascade that can promote dendritic cell maturation [11], [12] and culminate in the priming of tumor-specific T cells [13]C[15]. It has been hoped that this immune response would then have secondary beneficial effects on metastatic disease, progression of which is the most common cause of cancer-related deaths. Unfortunately, few local therapies have led to disease eradication by any immune response they putatively induce. We, therefore, Fos examined in greater detail the immune sequelae induced in the wake of local tumor ablation using hyperthermia with the goal of harnessing stimulatory immune components that could be exploited for the eradication of metastatic disease. We characterized the inflammatory and antitumor immune response to B16-F10 melanoma induced by gold nanoshell-enabled photothermal therapy (PTT), an ablation strategy that utilizes optically tuned gold nanoshells that generate heat upon exposure to near infrared radiation [16], [17]. To evaluate the antitumor effects initiated by PTT, we assessed the growth of distant tumor metastases following primary tumor ablation and identified both stimulatory and inhibitory immune components induced by PTT that promote or suppress immune responses. To enhance systemic antitumor effects, we determined if the immunostimulatory environment induced by PTT could be exploited to promote the expansion and function of adoptively Y16 transferred tumor-specific T cells. We found that PTT promoted the expression of proinflammatory cytokines and chemokines and induced the maturation of dendritic cells (DC) within tumor-draining lymph nodes. These effects did indeed lead to the priming of antitumor CD8+ effector T cell responses. Unfortunately, this response also promoted the generation of myeloid-derived suppressor cells and subsequently Y16 enhanced metastatic tumor growth. The effects of PTT were, however, sufficient to promote the expansion and function of adoptively transferred tumor-specific T cells, such that the combination of PTT and adoptive T cell therapy (ATCT), but not either component alone, benefited both local and metastatic disease. These data suggest Y16 that tumor ablation and adoptive immunotherapy can act in a complementary fashion and may be of value for treatment of human cancer. Materials and Methods Mice C57BL/6J, Albino C57BL/6J-Tyr-2J/J, and B6.Cg-Thy1a/Cy Tg(TcraTcrb)8Rest/J [18] mice were purchased from Jackson Laboratories (Bar Harbor, ME) and maintained in a pathogen-free mouse facility at Baylor College of Medicine according to institutional guidelines. This study was carried out in strict accordance with the recommendations of the Guide for the.
Category: Endothelin Receptors
Therefore, ideally HIV-infected individuals should be identified and encouraged to initiate ART as soon as possible, in order to avoid the destruction of thymic function. HIV infection evoked a generalized activation of the immune system, and a higher level of T-cell activation has been associated with a reduced recovery of the CD4+T-cell counts, increased mortality, and cardiovascular diseases.[16,21C23,37C40] Abnormal activation can increase HIV replication promote cell apoptosis, accelerate cell senescence, and cellular exhaustion, and it has also been associated with the HIV reservoir size.[41C43] We observed that although the activation of CD4+T cells was less intensive in individuals with early ART than in those receiving later ART, it still remained elevated when compared with NC. those with later ART (was used to compare between 2 groups of subjects. The KruskalCWallis and MannCWhitney tests were used to compare among the multiple groups of subjects. All tests were 2-tailed, and P?FSCN1 all the 78 patients increased from 243 to 413 cells/L. The elevation in CD4+T-cell counts was most prominent during the first 3 months after ART initiation (mean change 136 cells/L). After the first 3 months, CD4+T-cell counts became relatively stable (Fig. ?(Fig.11A). Open in a separate window Figure 1 Trajectories of CD4+T-cell counts during early antiretroviral therapy (ART) and later ART. (A) Trajectory of CD4+T-cell counts in patients with ART (n?=?78, mean values??standard deviation (SD) are shown in the figure). (B) Trajectories of CD4+T-cell counts in individuals initiating ART??6 months of infection (early ART, red, n?=?33), or 1 years after initial infection (later ART, blue, n?=?45, mean values are shown in figure). (C) Monthly changes of CD4+T-cell counts (CD4+T/month) were compared between early ART (red, n?=?33) and later ART (blue, n?=?45) (mean values??SD are shown in figure). Contribution of individuals with different CD4+T-cell changes (CD4+T) to the overall total after 12 months of early ART (D) or later ART (E). ?P?P?P?=?.012); in addition, at the 3rd and 12th month, CD4+T/month count in the early ART were significantly higher than those in later ART (57??44 vs 37??24 cells/L, P?=?.011; 18??12 vs 12??9 cells/L, P?=?.008) (Fig. ?(Fig.11C). Furthermore, after 12 months of ART, patients with CD4+T-cell counts change from baseline (CD4+T) greater than 300 cells/L, were observed in 33% of the early ART cases but K-Ras-IN-1 only 9% in those with later ART; in contrast, CD4+T less than 100 cells/L were detected in 21% of the early ART cases but almost double that number (38%) when the ART was initiated later (Fig. ?(Fig.1D1D and E). In summary, individuals with ART that had been initiated in the primary stage had K-Ras-IN-1 not only a greater CD4+T-cell count, but also a faster rate of CD4+T-cell recovery than those in whom ART started later. 3.2. Early ART restores more CD4+TN cells In addition to cell count, another important factor that contributes to CD4+T-cell functioning is the subset construction. We analyzed the CD4+T-cell subsets in patients receiving either early or later ART. By using CD45RA and CCR7, 3 CD4+T-cell subsets could be identified in human peripheral blood samples: TN, TEM, and TCM (Fig. ?(Fig.2A).2A). The percentage of CD4+TN in early ART was higher than that observed in later ART (P?=?.023), and it was similar to the situation in NC, and the percentage of CD4+TN in later ART and CHI were lower than those detected in the NC (P?=?.001; P?=?.04, respectively); in comparison with CHI, CD4+TN in PHI was higher (P?=?.036) (Fig. ?(Fig.2B).2B). The percentage of CD4+TEM K-Ras-IN-1 in CHI was higher than the corresponding values in PHI and NC (P?=?.013; P?=?.003, respectively), and the percentage of CD4+TEM in the early ART was not different from the NC; however, the percentage of CD4+TEM in later ART was higher than that in NC (P?=?.003) (Fig. ?(Fig.2D).2D). The percentage of CD4+TCM in later ART was higher than the corresponding values in CHI and NC (P?=?.003; P?=?.047, respectively) (Fig. ?(Fig.2C).2C). HIV-infected individuals receiving early ART had higher CD4+TN values and lower CD4+TEM in comparison with later ART. Open in a separate window Figure 2 Percentage of CD4+T-cell subsets and CD31+CD4+ naive T cell (TN) counts in patients receiving early antiretroviral therapy (ART) or.