A Population of Tumor-Infiltrating CD4+ T Cells Co-Expressing CD38 and CD39 Is Associated with Checkpoint Inhibitor Resistance.

PURPOSE: We previously showed that elevated frequencies of peripheral blood CD3+CD4+CD127-GARP-CD38+CD39+ T cells were associated with checkpoint immunotherapy resistance in patients with metastatic melanoma. In the present study, we sought to further investigate this population of ectoenzyme-expressing T cells (Teee). EXPERIMENTAL DESIGN: Teee derived from the peripheral blood of patients with metastatic melanoma were evaluated by bulk RNA-sequencing (RNA-seq) and flow cytometry. The presence of Teee in the tumor microenvironment was assessed using publically available single-cell RNA-seq datasets of melanoma, lung, and bladder cancers along with multispectral immunofluorescent imaging of melanoma patient formalin-fixed, paraffin-embedded specimens. Suppressive function of Teee was determined by an in vitro autologous suppression assay. RESULTS: Teee had phenotypes associated with proliferation, apoptosis, exhaustion, and high expression of inhibitory molecules. Cells with a Teee gene signature were present in tumors of patients with melanoma, lung, and bladder cancers. CD4+ T cells co-expressing CD38 and CD39 in the tumor microenvironment were preferentially associated with Ki67- CD8+ T cells. Co-culture of patient Teee with autologous T cells resulted in decreased proliferation of target T cells. High baseline intratumoral frequencies of Teee were associated with checkpoint immunotherapy resistance and poor overall survival in patients with metastatic melanoma. CONCLUSIONS: These results demonstrate that a novel population of CD4+ T cells co-expressing CD38 and CD39 is found both in the peripheral blood and tumor of patients with melanoma and is associated with checkpoint immunotherapy resistance.

Newly emerged immunogenic neoantigens in established tumors enable hosts to regain immunosurveillance in a T-cell-dependent manner.

Tumor neoantigens derived from genetic alterations are potential T-cell targets for antitumor immunity. However, tumors develop immune escape mechanisms including loss of preexisting neoantigens and/or impairment of T-cell responses during tumor development and progression. Here, we addressed whether newly emerged immunogenic neoantigens in established tumors enabled hosts to inhibit tumor growth via controlling immune escape mechanisms. Using a doxycycline-driven gene expression system, we generated murine MC38, CT26 (colorectal cancer) and B16 (melanoma) cell lines with inducible expression of model immunogenic neoantigens such as chicken ovalbumin and human NY-ESO-1. A model neoantigen was induced by doxycycline administration in the tumors once tumors became palpable. Tumor growth was significantly inhibited upon induction of the neoantigen and this inhibition was abrogated in nude mice lacking T cells and in mice deprived of CD8+ T cells, indicating the critical role of CD8+ T cells in tumor regression. In addition, PD-1/PD-L1 blockade further augmented the antitumor immune response, resulting in a far stronger inhibition of tumor growth. Accordingly, newly emerged tumor neoantigen-specific CD8+ T cells with enhanced effector functions were significantly increased in mice treated with PD-1/PD-L1 blockade. We propose that a newly emerged neoantigen is sufficient to inhibit tumor growth via preventing immune escape in a T-cell-dependent manner. Our results imply that induction of immunogenic tumor neoantigens is a novel strategy to overcome the resistance to immune checkpoint blockade therapy.

A case of advanced prostate cancer controlled for the long term by flutamide after bicalutamide failure.

Currently, the early introduction of new antiandrogens is popular for castration-resistant prostate cancer (CRPC). However, adverse events can be severe and their costs are high. Here, we present a patient with CRPC in whom flutamide controlled disease progression for 10 years. This case report shows that conventional alternative antiandrogens are cost effective and are still an important option for the treatment for CRPC.

[TWO CASES OF URETHRAL PROLAPSE MISDIAGNOSED AS PELVIC ORGAN PROLAPSE].

We experienced two cases of urethral prolapse misdiagnosed as pelvic organ prolapse. One patient, an 87-year-old woman, was referred to us from a gynecological clinic with a supposed uterine prolapse. The other patient, an 84-year-old woman, was referred to us from the Department of Urology in a general hospital with a supposed recurrence of cystocele following a transvaginal mesh repair. We diagnosed both of them as having a urethral prolapse through pelvic examination and cystoscopy. Both patients were treated uneventfully with the four-quadrant excisional technique. Urethral prolapse is a relatively rare disease and as such, urologists and gynecologists may have little exposure to the symptoms in a clinical setting, resulting to misdiagnosis or delayed diagnosis. We discussed the differential diagnosis of urethral prolapse.