Biology subjects

Fecci, P. E.

Publications and source records attributed to Fecci, P. E..

6 recordsLinked to original sources

bioRxiv2024

TNFR2 loss leads to decreased TOX expression in T cells without affecting TIM3 and improves responses to tumor and chronic LCMV

Exhaustion represents a collection of programmed T cell differentiation states and an important mode of T cell dysfunction. T cell progression from progenitor to terminal exhaustion is associated with upregulation of the transcription factor TOX and expression of TIM3. Our understanding of factors regulating TOX expression and the transition from progenitor to terminal exhaustion, however, remains incomplete. We reveal here that T cell upregulation of tumor necrosis factor receptor type II (TNFR2) coincides with the gain of phenotypic markers and functions reflective of terminal exhaustion. Meanwhile, knocking out TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and functional characteristics of both progenitor and terminally exhausted cells. TIM3+ TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of tumor and chronic lymphocytic choriomeningitis (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models.

immunology↗

bioRxiv2024

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies. Brief SummaryT cell immunotherapies are limited by few T cells in glioma. Adoptively transferred lymphocytes expanded with IL-7 exhibit increased VLA-4 expression and accumulate in tumors.

cancer biology↗

bioRxiv2023

Intracranial tumors elicit systemic sympathetic hyperactivity that limits immunotherapeutic responses

Intracranial tumors present unique challenges for immunotherapy. These can include both local and systemic modes of immune suppression whose mechanistic underpinnings are incompletely understood. Here, we reveal that tumors harbored intracranially elicit systemic increases to circulating catecholamine levels, with the resultant chronic sympathetic hyperactivity driving T cell dysfunction and limiting immunotherapeutic success. Conversely, treatment with {beta}-adrenergic blockade increases NF-{kappa}B activity in immune cells, restores T cell polyfunctionality, modifies the tumor microenvironment, and licenses immune-based therapies in murine models of glioblastoma (GBM) to extend survival. Extended survival is also observed in GBM patients having received {beta}-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received {beta}-blockade alongside concomitant immune checkpoint inhibition. While {beta}-blockade also impacts outcomes in the setting of extracranial disease, the benefits are especially pronounced in patients harboring intracranial disease burdens. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors, specifically and advance a role for {beta}-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.

immunology↗

bioRxiv2023

Antigen presentation by tumor-associated macrophages mediates progenitor to terminal exhaustion transition in GBM and other solid tumors

Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAM) - not tumor cells - were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to PD-1 immunotherapy. Thus, targeting TAM - T cell interactions may further license checkpoint blockade responses.

immunology↗

bioRxiv2023

A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8+ T Cells

The accepted paradigm for both cellular and antitumor immunity relies upon tumor cell kill by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex class I (MHC I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent on interactions between T cell NKG2D and tumor NKG2D ligands (NKG2DL). Necessarily, tumor cell kill in these instances is antigen-independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumors cells. These mechanisms are active in vivo in mice, as well as in vitro in human tumor systems, and are obviated by NKG2D knockout or blockade. Tumor cell killing following T cell NKG2D engagement is Fas-independent and appears to involve granzyme. These studies potentially obviate the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape, and instead identify the NKG2D/NKG2DL axis as a novel therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC loss variants.

immunology↗

bioRxiv2020

Preclinical modeling of surgery and steroid therapy for glioblastoma reveals changes in immunophenotype that are associated with tumor growth and outcome

Recent advances in cancer immunotherapy have created a greater appreciation of potential anti-tumoral impacts by the immune system; however, individual patient responses have been variable. While immunotherapy is often given after standard-of-care treatment, the effects of initial interventions on the ability of the immune system to mount a response are not well understood and this may contribute to the variable response. For glioblastoma (GBM), initial disease management includes surgical resection, perioperative high-dose steroid therapy, chemotherapy, and radiation treatment. While new discoveries regarding the impact of chemotherapy and radiation on immune response have been made and translated to clinical trial design, the impact of surgical resection and steroids on the anti-tumor immune response has yet to be determined. Further, it is now accepted that steroid usage needs to be closely evaluated in the context of GBM and immunotherapy trials. To better model the clinical scenario in GBM, we developed a mouse model that integrates tumor resection and steroid treatment to understand how these therapies affect local and systemic immune responses. Using this model, we observed a systemic reduction in lymphocytes associated with surgical resection and identified a correlation between increased tumor volume and decreased circulating lymphocytes, a relationship that was obviated by dexamethasone treatment. Furthermore, we investigated the possibility of there being similar relationships in a cohort of patients with GBM and found that prior to steroid treatment, circulating lymphocytes inversely correlated with tumor volume. Lastly, correlating GBM patient data and outcomes demonstrated that peripherally circulating lymphocyte content varies with progression-free and overall survival, independent of tumor volume, steroid use, or tumor molecular profiles. These results highlight the systemic immunosuppressive effects that initial therapies can have on patients. Such effects should be considered when designing current and future immunotherapy clinical trials and underscore the importance of circulating lymphocytes as a possible correlate of GBM disease progression.

cancer biology↗