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Fine-tuning Tumor Immunity with Integrin Trans-regulation.

ABSTRACT: Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. ?L?2 and ?4?1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting protein kinase A (PKA)-mediated phosphorylation of ?4 integrin in cells results in an increase in ?L?2-mediated migration on mixed ICAM-1-VCAM-1 substrates in vitro, a phenomenon termed "integrin trans-regulation." Here, we created an ?4(S988A)-bearing mouse, which precludes PKA-mediated ?4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The ?4(S988A) mouse exhibited a dramatic and selective increase in migration of lymphocytes, but not myeloid cells, to sites of inflammation. Importantly, we found that the ?4(S988A) mice exhibited a marked increase in T-cell entry into and reduced growth of B16 melanomas, consistent with antitumor roles of infiltrating T cells and progrowth functions of tumor-associated macrophages. Thus, increased ?4 trans-regulation of ?L?2 integrin function biases leukocyte emigration toward lymphocytes relative to myeloid cells and enhances tumor immunity.

SUBMITTER: Cantor JM

PROVIDER: S-EPMC5955000 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Fine-tuning Tumor Immunity with Integrin Trans-regulation.

Cantor Joseph M JM Rose David M DM Slepak Marina M Ginsberg Mark H MH

Cancer immunology research 20150119 6

Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. αLβ2 and α4β1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting protein kinase A (PKA)-mediated phosphorylation of α4 integrin in cells results in an increase in αLβ2-mediated migration on mixed ICAM-1-VCAM-1 substrates in vitro, a phenomenon termed "integrin trans-regulation." Here, we created an α4(S988A)-bearing mouse, which precludes PKA ...[more]

PMID: 25600437

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Project description:BackgroundAnti-tumor therapies aim at reducing to zero the number of tumor cells in a host within their end or, at least, aim at leaving the patient with a sufficiently small number of tumor cells so that the residual tumor can be eradicated by the immune system. Besides severe side-effects, a key problem of such therapies is finding a suitable scheduling of their administration to the patients. In this paper we study the effect of varying therapy-related parameters on the final outcome of the interplay between a tumor and the immune system.ResultsThis work generalizes our previous study on hybrid models of such an interplay where interleukins are modeled as a continuous variable, and the tumor and the immune system as a discrete-state continuous-time stochastic process. The hybrid model we use is obtained by modifying the corresponding deterministic model, originally proposed by Kirschner and Panetta. We consider Adoptive Cellular Immunotherapies and Interleukin-based therapies, as well as their combination. By asymptotic and transitory analyses of the corresponding deterministic model we find conditions guaranteeing tumor eradication, and we tune the parameters of the hybrid model accordingly. We then perform stochastic simulations of the hybrid model under various therapeutic settings: constant, piece-wise constant or impulsive infusion and daily or weekly delivery schedules.ConclusionsResults suggest that, in some cases, the delivery schedule may deeply impact on the therapy-induced tumor eradication time. Indeed, our model suggests that Interleukin-based therapies may not be effective for every patient, and that the piece-wise constant is the most effective delivery to stimulate the immune-response. For Adoptive Cellular Immunotherapies a metronomic delivery seems more effective, as it happens for other anti-angiogenesis therapies and chemotherapies, and the impulsive delivery seems more effective than the piece-wise constant. The expected synergistic effects have been observed when the therapies are combined.

Project description:Dendritic cells (DCs) are the sentinels of the mammalian immune system and they undergo a complex maturation process mediated by activation upon pathogen detection. Recent studies described the analysis of activated DCs by transcriptional profiling, but translation regulation was never taken in account. Therefore, the nature of the mRNAs being translated at various stages of DC activation was determined with the help of translational profiling, which is the sucrose gradient fractionation of polysomal-bound mRNAs combined to microarrays analysis. Total and polysomal-bound mRNA populations were compared in immature (0h) and LPS-stimulated (4h and 16h) human monocyte-derived DCs with the help of Affymetrix microarrays. Biostatistical analysis indicated that 296 mRNA molecules are translationally regulated during DC-activation. The most abundant biological process among the regulated mRNAs was protein biosynthesis, indicating the existence of a negative feedback loop regulating translation. Interestingly, a cluster of 17 ribosomal proteins were part of the regulated mRNAs, indicating that translation may be fine-tuned by particular components of the translational machinery. Our observations highlight the importance of translation regulation during the immune response, and may favour the identification of novel gene clusters or protein networks relevant for immunity. Our study also provides information on the possible absence of correlation between gene expression and real protein production in DCs. To identify translationally regulated mRNA molecules, gene expression derived from the polysome-bound mRNAs was compared by Affymetrix microarrays analysis to the gene expression derived from unfractionated total mRNAs derived from whole-cell lysates, as recently described on several reports (Johannes 1999, Rajasekhar 2003, Bushell 2006, Lü 2006, Parent 2008). Polysomal RNA (P) and total RNA (T) were isolated from MoDCs generated from four different blood donors. Since three timepoints (0h, 4h and 16h) were chosen for each blood donor and RNA type, twenty-four RNA samples were totally analyzed by microarrays.

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Fine-tuning Tumor Immunity with Integrin Trans-regulation.

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Fine-tuning Tumor Immunity with Integrin Trans-regulation.

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