Abstract Background Checkpoint blockade (CPB) has limited efficacy in patients with colorectal cancer (CRC), warranting improved therapeutic strategies capable of remodeling the tumor microenvironment. Stem-like TCF1+CD8+ T cells, cytotoxic CD8+ T cells, and lymphoid aggregates have been associated with CPB responsiveness, either individually or as coordinated immune hubs. Methods We evaluated the combination of αPD-1, the class I histone deacetylase inhibitor entinostat, and the IL-15 superagonist N-803 in CPB-resistant murine CRC and breast cancer models with varying antigen presentation deficiencies. Proteomic, transcriptomic, spatial, and functional analyses were completed to identify treatment-specific immune remodeling. Translational relevance was assessed using publicly available CPB-treated cancer genomic datasets and functional assays with patient-derived peripheral blood mononuclear cells (PBMCs). Results Triple therapy increased stem-like TCF1+CD8+ T cells in tumor-draining lymph nodes and tumors, concomitant with increased intratumoral cytotoxic GZMB+CD8+ T cells. Therapeutic efficacy was associated with remodeling of the tumor microenvironment, uniquely marked by enrichment of intratumoral immune niches comprising TCF1+ and cytotoxic CD8+ T cells, type 1 conventional dendritic cells, and B cells, along with concerted cytokine and chemokine production. A transcriptional signature derived from triple therapy-induced immune niches predicted favorable clinical responses across multiple CPB-experienced cancer cohorts. These responses were functionally corroborated by increased markers of cytotoxicity in patient-derived PBMCs in vitro. Conclusions Treatment with entinostat, N-803, and αPD-1 boosts anti-tumor intratumoral immune niches comprising TCF1+CD8+ T cells. Collectively, these findings suggest that TCF1+CD8+ T cell immune niches previously associated with αPD-1 responsiveness and lacking in non-responders, including most CRC patients, may be restored by the addition of entinostat and N-803 to αPD-1 therapy to treat αPD-1-refractory patients.
C. Minnar, Masaya Miyamoto, Asma S. Khelifa et al.· Journal for ImmunoTherapy of...· 0 citations
Endogenous retroviruses (ERVs) are remnants of germline retroviral infections that occurred over evolution and make up 5—8% of the human genome. Although ERVs are typically epigenetically silenced in healthy adult tissues, they are overexpressed in carcinomas and may represent a novel pool of immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a therapeutic target in cancer.
The expression of ERVMER34-1 in healthy adult and cancer tissues was assessed by IHC. Its immunogenicity in human PBMCs was evaluated by ELISPOT assays, and the lytic ability of specific T cells was assessed by live-cell imaging assays. In addition, a rationally designed ERVMER34-1—targeted therapeutic vaccine was tested for its ability to induce tumor clearance in two murine carcinoma models, as monotherapy or in combination with immuno-oncology agents.
The ERVMER34-1 protein is overexpressed in several human carcinomas while being absent in most healthy adult tissues. ERVMER34-1—specific T cells were detected in PBMCs of cancer patients but not healthy donors after overnight stimulation, yet reactive T cells expand readily from both groups after 7 days of in-vitro stimulation. These T cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A rationally designed therapeutic vaccine targeting ERVMER34-1 mediated tumor control in two syngeneic murine tumors. When combined with checkpoint blockade, the vaccine induced tumor regression and promoted the expansion of neoepitope-reactive T cells, whose function was further enhanced by an FDA-approved IL-15 superagonist. The strong neoepitope response associates with an inflamed tumor microenvironment marked by increased CD8+ T-cell infiltration and improved tumor control.
This study supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1, which would represent a new class of therapeutic cancer vaccine targeting ERVs.
This study was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
D. Hamilton, Maria del Mar Maldonado, Renee N. Donahue et al.· Journal of Immunology· 0 citations
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