Tissue-resident Tcells Research Articles

Single-cell sequencing links multiregional immune landscapes and tissue-resident Tcells in ccRCC to tumor topology and therapy efficacy.

Clear cell renal cell carcinomas (ccRCCs) are highly immune infiltrated, but the effect of immune heterogeneity on clinical outcome in ccRCC has not been fully characterized. Here we perform paired single-cell RNA (scRNA) and Tcell receptor (TCR) sequencing of 167,283 cells from multiple tumor regions, lymph node, normal kidney, and peripheral blood of two immune checkpoint blockade (ICB)-naïve and four ICB-treated patients to map the ccRCC immune landscape. We detect extensive heterogeneity within and between patients, with enrichment of CD8A+ tissue-resident Tcells in a patient responsive to ICB and tumor-associated macrophages (TAMs) in a resistant patient. A TCR trajectory framework suggests distinct Tcell differentiation pathways between patients responding and resistant to ICB. Finally, scRNA-derived signatures of tissue-resident Tcells and TAMs are associated with response to ICB and targeted therapies across multiple independent cohorts. Our study establishes a multimodal interrogation of the cellular programs underlying therapeutic efficacy in ccRCC.

Ovarian Cancer Immunogenicity is Governed by a Narrow Subset of Progenitor Tissue-Resident Memory T-Cells

Despite repeated associations between T-cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that hallmarks of tumor recognition in ovarian cancer-infiltrating T-cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3+CD8+CD103+CD69+ TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers showed that only progenitor (TCF1low) tissue-resident T-cells (TRMstem cells), but not re-circulating TCF1+ T-cells, predict ovarian cancer outcome. TRMstem cells arise from transitional re-circulating T-cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease that depends on ~13% of CD8+ tumor-infiltrating T-cells (~3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM cells.

Paying the Toll for Inflammation

Paying the Toll for Inflammation

Contemporary HIV Vaccines: Tissue Resident T-Cells and Strategies to Prevent Mucosal Infection.

HIV is primarily transmitted to women via the cervicovaginal mucosa, with the infection remaining localized for several days prior to systemic dissemination and irreversible damage to the immune system. The early phase during which HIV infection is localized and exhibits little or no viral diversity presents a vantage point for HIV vaccines that stimulate T-cell mediated clearance. CD(8+) resident memory T-cells (TRM) are positioned at mucosal entry sites and are established upon resolution of infection by mucosal pathogens. TRM cells are long-lived and locally patrol mucosal tissues. Upon antigenic reactivation, the sentinel-like functions of TRM cells mediate rapid clearance of subsequent infection by recruitment of additional immune cells from circulation and initiate a tissue-wide antiviral state, thus preventing the recurrence of disease. These properties are ideally suited for an HIV vaccine aimed at halting the infection cycle of HIV during the earliest phases. In this review, we summarize recent vaccine developments from parallel research areas incorporating the use of live mucosal vectors complemented with chemokine-regulating compounds, which can induce the seeding of the vaginal mucosa with TRM cells. We present the proposition that similar novel vaccine regimens can be translated into approaches for future HIV vaccines aimed at inducing heightened immunity in vaginal tissues against HIV.