Adequate Antigen Availability: A Key Issue for Novel Approaches to Tumor Vaccination and Tumor Immunotherapy

A crucial parameter for activation of the anti-tumor immune response is an adequate antigen availability (AAA) defined here as the optimal tumor antigen dose and related antigen processing and MHC-II-restricted presentation necessary to efficiently trigger tumor-specific TH cells. We will discuss two distinct experimental systems: a) a preventive anti-tumor vaccination system; b) a therapy-induced anti-tumor vaccination approach. In the first case tumor cells are rendered constitutively MHC-II+ by transfecting them with the MHC-II transcriptional activator CIITA. Here AAA is generated by the function of tumor's newly expressed MHC-II molecules to present tumor-associated antigens to tumor-specific TH cells. In the second case, AAA is generated by treating established tumors with neovasculature-targeted TNF alpha. In conjuction with Melphalan, targeted TNF alpha delivery produces extensive areas of tumor necrosis that generate AAA capable of optimally activate tumor-specific TH cells which in turn activate CTL immune effectors. In both experimental systems tumor rejection and persistent and long-lived TH cell anti-tumor memory, responsible of defending the animals from subsequent challenges with tumor cells, are achieved. Based on these and other investigators' results we propose that AAA is a key element for triggering adaptive immune functions resulting in subversion from a pro-tumor to an anti-tumor microenvironment, tumor rejection and acquisition of anti-tumor immune memory. Hypotheses of neuro-immune networks involved in these approaches are discussed. These considerations are important also for the comprehension of how chemotherapy and/or radiation therapies may help to block and/or to eradicate the tumor and for the construction of suitable anti-tumor vaccine strategies

A dual defensive role of CIITA against retroviral infections

We describe how CIITA exerts a dual role against retroviral infection. The first, classical role is the upregulation of MHC class II expression and thus the capacity to present viral antigens to CD4+ T cells. The other, evolutionary new and fundamental role is to inhibit viral replication by blocking specifically the function of the viral transactivators. HIV-1 Tat is inhibited through the competition for cyclin T1 of the P-TEFb complex, whereas HTLV-2 Tax-2 is inhibited through a concerted action which may increase the binding affinity of the CIITA-NFY complex for Tax-2, displacing it from the viral LTR promoter. As expected, two distint sequences in the N-term region of CIITA mediate the inhibitory action on Tat and Tax-2, respectively. Of note, Tax-1 from HTLV-1 seems also to be inhibited by the same sequence that inhibits HTLV-2 Tax-2. Interestingly, only those CIITA fragments containing the minimal inhibitory domains that localize into the nucleus could exert an effective suppressive action. Taken together, our results indicate that CIITA is an extant molecular tool endowed with distinct evolving functions against retroviruses. These distinct properties of CIITA will shed new light on the molecular mechanisms of adaptive coevolution of hosts and pathogens and may be exploited to envisage novel therapeutic strategies aimed at counteracting retroviral infections

Structure and regulation of MHC system

A short review about the molecular structure of MHC class II genes and their regulation at the transcription level