Vaccines that promote protective adaptive immune responses have been successfully developed against a range of infectious diseases, and these are normally administered prior to exposure with the relevant virus or bacteria. Adaptive immunity also plays a critical role in the control of tumors. Immunotherapeutics and vaccines that promote effector T cell responses have the potential to eliminate tumors when used in a therapeutic setting. However, the induction of protective antitumor immunity is compromised by innate immunosuppressive mechanisms and regulatory cells that often dominate the tumor microenvironment. Recent studies have shown that blocking these suppressor cells and immune checkpoints to allow induction of antitumor immunity is a successful immunotherapeutic modality for the treatment of cancer. Furthermore, stimulation of innate and consequently adaptive immune responses with concomitant inhibition of immune suppression, especially that mediated by regulatory T (Treg) cells, is emerging as a promising approach to enhance the efficacy of therapeutic vaccines against cancer. This review describes the immunosuppressive mechanisms controlling antitumor immunity and the novel strategies being employed to design effective immunotherapeutics against tumors based on inhibition of suppressor cells or blockade of immune checkpoints to allow induction of more potent effector T cell responses. This review also discusses the potential of using a combination of adjuvants with inhibition of immune checkpoint or suppressor cells for therapeutic vaccines and the translation of pre--clinical studies to the next--generation vaccines against cancer in humans

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IntroductionInterstitial lung diseases (ILD) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein complex (SP)-A. Only 11 SFTPA1/2 mutations have so far been reported worldwide, of which 5 have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.MethodsThe consequences of the 11 SFTPA1/2 mutations were analysed both in vitro by studying the production and secretion of the corresponding mutated proteins and ex vivo by analysing SP-A expression on lung tissue samples. The associated disease phenotypes were documented.ResultsFor the 11 identified mutations, protein production was preserved, but secretion was abolished. The expression pattern of lung SP-A, available in 6 patients, was altered. The family history reported ILD and/or lung adenocarcinoma in 13/14 (93%) families. Among the 28 SFTPA1/2 mutation carriers, the mean age at ILD onset was 45 [0.6–65] years and 48% of them underwent lung transplantation (mean age 51); 7 carriers were asymptomatic.DiscussionThis study, which expands the molecular and clinical spectrum of SP-A disorders, shows that those pathogenic SFTPA1/A2 mutations share similar consequences on SP-A secretion in cell models and lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of the disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.