Background: Androgen receptor (AR) inactivation causes telomere dysfunction. Results: AR-inactivation-induced telomere dysfunction led to the activation of ATM at telomeres, and ATM inhibition blocked repair of damaged telomeric DNA and augmented cell death. Conclusion: ATM promotes survival of AR-inactivated prostate cancer cells with telomere dysfunction. Significance: ATM inhibitors may potentiate the efficacy of AR-targeted therapies for the treatment of prostate cancer.

Epidermal squamous cell carcinoma (SCC) is among the most common cancers. SCC can be treated by surgical excision, but recurrence of therapy-resistant disease is a major problem. We recently showed that YAP1, the Hippo signaling transcription adaptor protein, and ∆Np63α, a key epidermal stem cell survival protein, form a complex to drive epidermal cancer stem cell survival. In the present study, we demonstrate that YAP1 and ∆Np63α are important sulforaphane cancer prevention targets. We show that sulforaphane treatment increases YAP1 phosphorylation and proteolytic degradation. The loss of YAP1 is associated with a reduction in ∆Np63α level and a reduction in ECS cell survival, spheroid formation, invasion and migration. Loss of YAP1 and ∆Np63α is mediated by the proteasome and can be inhibited by lactacystin treatment. YAP1 or ∆Np63α knockdown replicates the responses to sulforaphane, and restoration of YAP1 or ∆Np63α antagonizes sulforaphane action. Sulforaphane suppresses ECS cell tumor formation and this is associated with reduced levels of YAP1 and ∆Np63α. These studies suggest that YAP1 and ∆Np63α may be important sulforaphane cancer preventive targets in epidermal squamous cell carcinoma.

Bi-specific T cell engagers (BiTEs) activate T cells through CD3 and target activated T cells to tumor-expressed antigens. BiTEs have shown therapeutic efficacy in patients with liquid tumors; however, they do not benefit all patients. Anti-tumor immunity is limited by Programmed Death 1 (PD1) pathway-mediated immune suppression, and patients who do not benefit from existing BiTES may be non-responders because their T cells are anergized via the PD1 pathway. We have designed a BiTE that activates and targets both T cells and NKT cells to PDL1+ cells. In vitro studies demonstrate that the CD3xPDL1 BiTE simultaneously binds to both CD3 and PDL1, and activates healthy donor CD4+ and CD8+ T cells and NKT cells that are specifically cytotoxic for PDL1+ tumor cells. Cancer patients’ PBMC are also activated and cytotoxic, despite the presence of myeloid-derived suppressor cells. The CD3xPDL1 BiTE significantly extends the survival time and maintains activated immune cell levels in humanized NSG mice reconstituted with human PBMC and carrying established human melanoma tumors. These studies suggest that the CD3xPDL1 BiTE may be efficacious for patients with PDL1+ solid tumors, in combination with other immunotherapies that do not specifically neutralize PD1 pathway-mediated immune suppression.

Cancer immunotherapies aimed at neutralizing the programmed death-1 (PD-1) immune suppressive pathway have yielded significant therapeutic efficacy in a subset of cancer patients. However, only a subset of patients responds to antibody therapy with either anti-PD-1 or anti-PD-L1 antibodies. These patients appear to have so-called “hot” tumors containing tumor-reactive T cells. Therefore, checkpoint blockade therapy may be effective in a larger percentage of cancer patients if combined with therapeutics that also activate tumor-reactive T cells. Radiotherapy (RT) is a prime candidate for combination therapy because it facilitates activation of both local antitumor immunity and antitumor immunity at non-radiated, distant sites (abscopal response). However, RT also promotes tumor cell expression of PD-L1 and facilitates the development of myeloid-derived suppressor cells (MDSC), a population of immune suppressive cells that also suppress through PD-L1. This article will review how RT induces MDSC, and then describe two novel therapeutics that are designed to simultaneously activate tumor-reactive T cells and neutralize PD-1-mediated immune suppression. One therapeutic, a CD3xPD-L1 bispecific T cell engager (BiTE), activates and targets cytotoxic T and NKT cells to kill PD-L1 + tumor cells, despite the presence of MDSC. The BiTE significantly extends the survival time of humanized NSG mice reconstituted with human PBMC and carrying established metastatic human melanoma tumors. The second therapeutic is a soluble form of the costimulatory molecule CD80 (sCD80). In addition to costimulating through CD28, sCD80 inhibits PD-1 suppression by binding to PD-L1 and sterically blocking PD-L1/PD-1 signaling. sCD80 increases tumor-infiltrating T cells and significantly extends survival time of mice carrying established, syngeneic tumors. sCD80 does not suppress T cell function via CTLA-4. These studies suggest that the CD3xPD-L1 BiTE and sCD80 may be efficacious therapeutics either as monotherapies or in combination with other therapies such as radiation therapy for the treatment of cancer.

Melanoma represents the most serious type of skin cancer. Although recent years have seen advances using targeted and immunotherapies, most patients remain at high risk for tumor recurrence. Here we show that IRAK-M, a negative regulator of MyD88 signaling, is deficient or low in melanoma and expression levels correlate with patient survival. Inducing IRAK-M expression using genetic approaches or epigenetic modifiers initiates apoptosis by prompting its interaction with TRAF6 via IRAK-M's C-terminal domain. This complex recruits and degrades calpastatin which stimulates calpain activity and triggers caspase-3-dependent but caspase-8,−9-independent apoptosis. Using a drug screen, we identified compounds that induced IRAK-M expression. Administration of IRAK-M-inducing drugs reduced tumor growth in mice but was ineffective against IRAK-M knock-down tumors. These results uncover a previously uncharacterized apoptosis pathway, emphasize IRAK-M as a potential therapeutic target and suggest that the anticancer activity of certain drugs could do so through their ability to induce IRAK-M expression.

Donor-derived lymphocytes from allogeneic hematopoietic cell transplantation (allo-HCT) or donor lymphocyte infusion can mediate eradication of host tumor cells in a process labeled the graft-versus-tumor (GVT) effect. Unfortunately, these treatments have produced limited results in various types of leukemia because of an insufficient GVT effect. In this context, molecular engineering of donor lymphocytes to increase the GVT effect may benefit cancer patients. Activating MyD88 signaling in CD8+ T cells via TLR enhances T cell activation and cytotoxicity. However, systemic administration of TLR ligands to stimulate MyD88 could induce hyperinflammation or elicit protumor effects. To circumvent this problem, we devised a synthetic molecule consisting of MyD88 linked to the ectopic domain of CD8a (CD8α:MyD88). We used this construct to test the hypothesis that MyD88 costimulation in donor CD8+ T cells increases tumor control following allo-HCT in mice by increasing T cell activation, function, and direct tumor cytotoxicity. Indeed, an increase in both in vitro and in vivo tumor control was observed with CD8α:MyD88 T cells. This increase in the GVT response was associated with increased T cell expansion, increased functional capacity, and an increase in direct cytotoxic killing of the tumor cells. However, MyD88 costimulation in donor CD8+ T cells was linked to increased yet nonlethal graft-versus-host disease in mice treated with these engineered CD8+ T cells. Given these observations, synthetic CD8α:MyD88 donor T cells may represent a unique and versatile approach to enhance the GVT response that merits further refinement to improve the effectiveness of allo-HCT.