Targeting PD-1/PD-L1 in lung cancer: current perspectives.

Increased understanding of tumor immunology has led to the development of effective immunotherapy treatments. One of the most important advances in this field has been due to pharmacological design of antibodies against immune checkpoint inhibitors. Anti-PD-1/PD-L1 antibodies are currently in advanced phases of clinical development for several tumors, including lung cancer. Results from Phase I-III trials with anti-PD-1/PD-L1 antibodies in non-small-cell lung cancer have demonstrated response rates of around 20% (range, 16%-50%). More importantly, responses are long-lasting (median duration of response, 18 months) and fast (50% of responses are detected at time of first tumor evaluation) with very low grade 3-4 toxicity (less than 5%). Recently, the anti-PD-1 antibody pembrolizumab received US Food and Drug Administration (FDA) breakthrough therapy designation for treatment of non-small-cell lung cancer, supported by data from a Phase Ib trial. Another anti-PD-1 antibody, nivolumab, has also been approved for lung cancer based on survival advantage demonstrated in recently released data from a Phase III trial in squamous cell lung cancer.

p85ß phosphoinositide 3-kinase subunit regulates tumor progression.

PIK3R2 encodes a ubiquitous regulatory subunit (p85ß) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85ß expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85ß expression induced moderate PIP(3) generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of pik3r2 expression levels modulated tumor progression in vivo. Increased p85ß expression thus represents a cellular strategy in cancer progression.

Ral GTPases regulate cell-mediated cytotoxicity in NK cells.

NK cells are key components of the immune response to virally infected and tumor cells. Recognition of target cells initiates a series of events in NK cells that culminates in target destruction via directed secretion of lytic granules. Ral proteins are members of the Ras superfamily of small GTPases; they regulate vesicular trafficking and polarized granule secretion in several cell types. In this study, we address the role of Ral GTPases in cell-mediated cytotoxicity. Using a human NK cell line and human primary NK cells, we show that both Ral isoforms, RalA and RalB, are activated rapidly after target cell recognition. Furthermore, silencing of RalA and RalB impaired NK cell cytotoxicity. RalA regulated granule polarization toward the immunological synapse and the subsequent process of degranulation, whereas RalB regulated degranulation but not polarization of lytic granules. Analysis of the molecular mechanism indicated that Ral activation in NK cells leads to assembly of the exocyst, a protein complex involved in polarized secretion. This assembly is required for degranulation, as interference with expression of the exocyst component Sec5 led to reduced degranulation and impaired cytotoxicity in NK cells. Our results thus identify a role for Ral in cell-mediated cytotoxicity, implicating these GTPases in lymphocyte function.

Phosphatidylinositol 3-kinase gamma inhibition ameliorates inflammation and tumor growth in a model of colitis-associated cancer.

BACKGROUND & AIMS: A large body of evidence supports a correlation between inflammation and cancer, although the molecular mechanisms that govern this process are incompletely understood. Phosphatidylinositol 3-kinase (PI3K) is an enzyme that regulates the immune response and contributes to cell transformation in several tumor types. Here, we address the role of the PI3Kgamma isoform in inflammatory bowel disease and in the development of colitis-associated cancer. METHODS: PI3Kgamma(-/-) and control mice were repeatedly treated with dextran sulfate sodium to induce chronic colitis and colitis-associated cancer. Colorectal tumor burden and colon inflammation were evaluated in these mice. Leukocyte populations in colon were characterized by flow cytometry analysis. RESULTS: PI3Kgamma-deficient mice had a lower incidence of colitis-associated tumors, as well as reduced tumor multiplicity and smaller tumor size compared with controls. Reduced tumor development paralleled less colon inflammation in PI3Kgamma-deficient mice. Analysis of leukocyte populations in the colon of PI3Kgamma-deficient mice showed defective activation and infiltration of myeloid cells and defective recruitment of T cells to the colon compared with controls. CONCLUSIONS: PI3Kgamma regulates the innate immune response in a murine model of ulcerative colitis, thereby controlling colon inflammation and tumor formation.

Drug-related hepatotoxicity and hepatic failure following combined androgen blockade.

Androgen deprivation therapy has been the mainstay of treatment for metastatic prostate cancer and of less advanced cancers as neoadjuvant and adjuvant treatment. Abnormal liver function test, in particular elevated transaminases, is an adverse reaction more frequently noticed during androgen deprivation therapy with antiandrogen. We report the case of a patient with acute hepatic failure associated with the use of bicalutamide.

On the association between chromosomal rearrangements and genic evolution in humans and chimpanzees.

BACKGROUND: The role that chromosomal rearrangements might have played in the speciation processes that have separated the lineages of humans and chimpanzees has recently come into the spotlight. To date, however, results are contradictory. Here we revisit this issue by making use of the available human and chimpanzee genome sequence to study the relationship between chromosomal rearrangements and rates of DNA sequence evolution. RESULTS: Contrary to previous findings for this pair of species, we show that genes located in the rearranged chromosomes that differentiate the genomes of humans and chimpanzees, especially genes within rearrangements themselves, present lower divergence than genes elsewhere in the genome. Still, there are considerable differences between individual chromosomes. Chromosome 4, in particular, presents higher divergence in genes located within its rearrangement. CONCLUSION: A first conclusion of our analysis is that divergence is lower for genes located in rearranged chromosomes than for those in colinear chromosomes. We also report that non-coding regions within rearranged regions tend to have lower divergence than non-coding regions outside them. These results suggest an association between chromosomal rearrangements and lower non-coding divergence that has not been reported before, even if some chromosomes do not follow this trend and could be potentially associated with a speciation episode. In summary, without excluding it, our results suggest that chromosomal speciation has not been common along the human and chimpanzee lineage.