Combining epigenetic and immune therapy to overcome cancer resistance.

Cancer undergoes "immune editing" to evade destruction by cells of the host immune system including natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Current adoptive cellular immune therapies include CAR T cells and dendritic cell vaccines, strategies that have yet to show success for a wide range of tumors. Cancer resistance to immune therapy is driven by extrinsic factors and tumor cell intrinsic factors that contribute to immune evasion. These extrinsic factors include immunosuppressive cell populations such as regulatory T cells (Tregs), tumor-associated macrophages (TAMS), and myeloid-derived suppressor cells (MDSCs). These cells produce and secrete immunosuppressive factors and express inhibitory ligands that interact with receptors on T cells including PD-1 and CTLA-4. Immune checkpoint blockade (ICB) therapies such as anti-PD-1 and anti-CTLA-4 have shown success by increasing immune activation to eradicate cancer, though both primary and acquired resistance remain a problem. Tumor cell intrinsic factors driving primary and acquired resistance to these immune therapies include genetic and epigenetic mechanisms. Epigenetic therapies for cancer including DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), and histone methyltransferase inhibitors (HMTi) can stimulate anti-tumor immunity in both tumor cells and host immune cells. Here we discuss in detail tumor mechanisms of immune evasion and how common epigenetic therapies for cancer may be used to reverse immune evasion. Lastly, we summarize current clinical trials combining epigenetic therapies with immune therapies to reverse cancer immune resistance mechanisms.

Non-Insulin Antidiabetic Agents and Lung Cancer Risk in Drug-Naive Patients with Type 2 Diabetes Mellitus: A Nationwide Retrospective Cohort Study.

Lung cancer (LC) is the second most common cancer and the leading cause of cancer deaths in the U.S. Insulin therapy, a key treatment for managing Type 2 Diabetes Mellitus (T2DM), is associated with increased LC risk. The impact of non-insulin antidiabetic drugs, particularly GLP-1 receptor agonists (GLP-1RAs), on LC risk is not well understood. This study evaluated LC risk in T2DM patients, comparing seven non-insulin antidiabetic agents to insulin. Using the TriNetX Analytics platform, we analyzed the de-identified electronic health records of 1,040,341 T2DM patients treated between 2005 and 2019, excluding those with prior antidiabetic use or LC diagnoses. We calculated hazard ratios and confidence intervals for LC risk and used propensity score matching to control for confounding factors. All non-insulin antidiabetic drugs, except alpha-glucosidase inhibitors, were associated with significantly reduced LC risk compared to insulin, with GLP-1RAs showing the greatest reduction (HR: 0.49, 95% CI: 0.41, 0.59). GLP-1RAs were consistently associated with lowered LC risk across all histological types, races, genders, and smoking statuses. These findings suggest that non-insulin antidiabetic drugs, particularly GLP-1RAs, may be preferable for managing T2DM while reducing LC risk.

Incidence of prostate cancer in transgender women in the US: a large database analysis.

The risk of prostate cancer among transgender women undergoing medical and surgical gender-affirming interventions remains unclear, though up to a fivefold decreased risk has been reported in comparison to cisgender men. In this study, we conducted a comparative analysis of the risk of prostate cancer among transgender women (TW) using data from TriNetX, a large database, versus SEER. Our findings indicate that, overall, transgender women exhibited a 2.56-fold lower risk of prostate cancer compared to cisgender men. Specifically, among TW on hormone therapy between ages 50-64, we observed a 2.06-fold decrease in risk. Contrary to the previous perception of prostate cancer being rare in transgender women, our study suggests that it may not be as uncommon as previously believed.

Rates of Urinary Tract Infection in Transgender Women Postvaginoplasty vs Cisgender Women: A Retrospective Cohort Study in a Large US Health Network.

OBJECTIVE: To describe urinary tract infection (UTI) risk 3-month postvaginoplasty (VP) in transgender women (TW) compared to cis women (CW). METHODS: Using TriNetX (TriNetX, Inc, Cambridge, MA), we built cohorts of 2041 TW and 48,374,745 CW. Outcomes were ≥1 instance of UTI or Cystitis, and assessed from 3-6, 3-12, 3-36months, and 3months-10years post-VP. TW and CW were age-cohorted (18-39, 40-59, 60-74) and compared at each time interval. Kaplan-Meier was used to account for loss to follow-up, along with hazard ratios and log-rank tests to determine significance (P <.05). RESULTS: For all time intervals and age ranges, TW had a significantly (P <.0001-P = .0088) higher probability of developing a UTI compared to CW. The largest difference was ages 40-59 ten-year post-VP. In this analysis, CW and TW had a 12.96% and 29.34% cumulative outcome incidence, respectively. Cox proportional hazard analysis demonstrated increased hazard for TW compared to CW. Hazard ratios between CW and TW ranged from 1.363 (ages 18-39 at 10years, 95%CI: 1.119,1.660) to 3.522 (ages 60-74 at 12months, 95%CI: 1.951,6.360). CONCLUSION: We found a significantly higher probability of TW developing UTIs compared to age-cohorted CW. Contributing factors may include difficulties with neovaginal perineal hygiene, lack of commensal bacteria and vaginal mucosa, larger urethral meatus, high rates of meatal stenosis, and nonnative bacteria introduced through dilators and douching. These findings may help improve quality of postoperative care in TW.