Biology subjects

Brandle, C.

Publications and source records attributed to Brandle, C..

3 recordsLinked to original sources

bioRxiv2026

IL13 critically contributes to the antitumor activity of polyfunctional CD4+ T cells driven by constitutively active Stat5

The presence of polyfunctional T cells capable of concurrently producing multiple cytokines correlates with favorable clinical outcomes in patients with cancer. We previously reported that overexpression of constitutively active Stat5a (CASTAT5) confers polyfunctionality on tumor-specific CD4 T cells, enabling durable antitumor immunity following adoptive cell therapy. However, the mechanisms underlying the enhanced antitumor effects of CASTAT5-modified T cells remain unclear. Here, we identify interleukin-13 (IL13) as a critical effector cytokine contributing to the multifaceted antitumor activity of CASTAT5-conditioned polyfunctional CD4 T cells (C5-CD4). C5-CD4 T cells exhibit a prominent T helper 2 (Th2) cytokine profile, accompanied by extensive epigenomic remodeling at the Th2 cytokine loci, as revealed by Hi-C and histone-modification CUT&Tag assays. Neutralization of IL13 diminished the antitumor efficacy of C5-CD4 T cells. Furthermore, targeted Il13 disruption substantially impaired tumor control and was associated with reduced donor T cell expansion and persistence, diminished systemic cytokine and chemokine responses, and attenuated activation of endogenous tumor-reactive CD8 T cells. Nonetheless, IL13 overexpression alone in donor CD4 T cells failed to fully recapitulate the therapeutic activity of C5-CD4 T cells, indicating that IL13 is a critical contributor but is insufficient to account for the full antitumor activity conferred by CASTAT5. Single-cell RNA sequencing associated donor-derived IL13 with increased representation of tumor-infiltrating myeloid cells and IL13-signaling in monocytes and macrophages exhibiting tissue-repair-associated transcriptional programs. Moreover, Il13 disruption diminished the therapeutic efficacy of CASTAT5-expressing CD19-targeted CAR-T cells in a mouse B-cell lymphoma model. Reanalysis of a human CD19CAR-T infusion-product dataset further revealed an association between IL13 expression and type 2 cytokine signatures linked to prolonged clinical response, suggesting a potential contribution of IL13 to the efficacy of human CD19CAR-T therapy. Together, these findings uncover an unexpected antitumor role for IL13 and establish it as a critical node linking polyfunctional donor T cells with endogenous immune cells to promote sustained tumor immunity.

immunology↗

bioRxiv2026

Targeting phosphodiesterase 10A disrupts MAPK signaling pathways in the tumor microenvironment to unleash antitumor immunity

Phosphodiesterase 10A (PDE10A), a cyclic nucleotide-degrading enzyme, is overexpressed in various human cancers. While PDE10A inhibition using small-molecule inhibitors or gene silencing suppresses tumor growth in xenograft models, its precise mechanism of action and immunological impact remain unclear. Here, we report that ADT-030, a novel PDE10A inhibitor, exhibits potent cytotoxicity against a broad range of murine tumor cell lines. ADT-030 is orally bioavailable and effectively suppresses tumor growth across multiple syngeneic mouse models. Notably, its efficacy is diminished in immunodeficient mice or upon CD8+ T cell depletion, highlighting a critical dependence on host immunity. The immunostimulatory properties of ADT-030 are further supported by its ability to induce immunogenic tumor cell death and promote dendritic cell (DC) maturation, its reliance on Batf3-expressing DCs to elicit antitumor CD8+ T cell response, and its synergy with anti-PD-1 therapy. Comprehensive immune profiling in the 4T1 breast cancer model, both in orthotopic and metastatic settings, revealed that ADT-030 selectively reduces myeloid-derived suppressor cells (MDSCs) while normalizing the immune landscape within the tumor. Mechanistically, ADT-030 disrupts multiple components of the mitogen-activated protein kinase (MAPK) signaling network in both tumor cells and MDSCs, leading to induction of apoptosis in these populations. These findings highlight the multi-faceted impact of PDE10A inhibition as a therapeutic strategy that not only disrupts tumor-intrinsic oncogenic signaling to inhibit tumor progression but also reshapes the tumor immune microenvironment to unleash antitumor immunity.

immunology↗

bioRxiv2026

Indomethacin exerts both cyclooxygenase inhibition-dependent and independent mechanisms to enhance chemo-immunotherapy in mice

Nonsteroidal anti-inflammatory drugs (NSAIDs) primarily act by inhibiting cyclooxygenases (COX1 and COX2), thereby reducing production of the proinflammatory mediator prostaglandin E2 (PGE2). Because PGE2 is a critical driver of cancer progression and tumor immune evasion, this has motivated interest in combining NSAIDs with chemotherapy or immunotherapy for cancer treatment. However, since COX and PGE2 levels vary across tumor types, it remains unclear whether tumor PGE2 abundance solely dictates tumor response to NSAID-based therapies. Here, we investigated the therapeutic potential of indomethacin (Indo), a prototypical NSAID, in combination with cyclophosphamide (CTX), a widely used chemotherapeutic agent with immunostimulatory properties. Metronomic administration of Indo significantly enhanced the antitumor efficacy of CTX in multiple murine tumor models exhibiting variable COX2 and PGE2 levels, including CT26, MC38, 4T1 and A20. The antitumor effects of CTX+Indo required CD8 T cells and T-cell trafficking from tumor-draining lymph nodes and were further potentiated by anti-PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that responsive CT26 tumors exhibited a reprogrammed tumor immune microenvironment (TIME), marked by increased effector CD8 T-cell infiltration, reduced immunosuppressive myeloid populations, and enhanced interferon signaling in tumor cells. Importantly, Indo retained therapeutic benefit following CTX even in tumors incapable of producing PGE2, demonstrating a critical contribution of COX-independent mechanisms, particularly inhibition of tumor-intrinsic oncogenic RAS signaling, to the enhanced efficacy of the CTX+Indo combination. Collectively, our results provide strong preclinical rationale for leveraging the COX/PGE2 and RAS dual inhibitory capacities of NSAIDs to enhance the efficacy of chemotherapy and immunotherapy.

immunology↗